CN105025933A - Triazine based radiopharmaceuticals and radioimaging agents - Google Patents
Triazine based radiopharmaceuticals and radioimaging agents Download PDFInfo
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Abstract
Compounds according to Formula (I) and Formula (II) are potent inhibitors of PSMA. (I) or (II) Pharmaceutical compositions may include a complex of a radionuclide and a Formula (I) compound or a Formula (II) compound. Methods include using the radionuclide complex of a Formula (I) compound or a Formula (II) compound for treating or diagnosis of a disease or a condition associated with PSMA activity.
Description
the cross reference of related application
This application claims the U.S. Provisional Patent Application the 61/752nd submitted on January 14th, 2013, the U.S. Provisional Patent Application the 61/785th that the rights and interests of No. 350 and on March 14th, 2013 submit to, the rights and interests of No. 788, the full content of these two U.S. Provisional Patent Application is incorporated to herein by reference.
Technical field
Technology of the present invention relates generally to radiopharmaceutical field and as the application in nuclear medicine of tracer, developing agent and the application in the various different morbid state for the treatment of.
Background technology
Many tumors all can express the protein of some uniquenesses, and the protein of these uniquenesses is indicators of malignant tumor and poor prognosis.These protein provide the mark these protein being used as cancer diagnosis disease and are used as the unique opportunity of sending target spot of radiation treatment agent with the progress of assessment of cancer disease and by these protein in the expression of tumor cell surface.The Geigers be optionally combined with specific tumors cell surface protein provides and under noinvasive condition, makes tumor imaging and the prominent approach for the treatment of tumor.Specifically, the invention provides radiolabeled part, this ligand specificity is in conjunction with prostate specific membrane antigen (PSMA) albumen, and this part process LAN on many cancerous cell, thus be used as medicament or the developing agent of the radiation therapy of the cancerous cell of expressing PSMA.
The existing man more than 1,000,000 suffers from carcinoma of prostate at present, according to estimates, in six U.S. men of 60 years old to 80 years old, just has one to suffer from this disease.Diagnose out more than 300 every year, the carcinoma of prostate new case of 000 example and the fatality rate of carcinoma of prostate is only second to pulmonary carcinoma, come second.The whole world at present cost about 2,000,000,000 dollars of operations being used for the treatment of carcinoma of prostate, radiotherapy and medicines.At present not used for carcinoma of prostate Preventive, do not rely on effective therapy of androgenic carcinoma of prostate.This area is needed badly at present and can be made carcinoma of prostate quick display and the new medicament in order to therapeutic purposes this cancerous tissue selectively targeted.
Human prostate-specific membrane antigen (PSMA), also referred to as folic acid hydrolytic enzyme 1 (FOLH1), cross-film, 750 aminoacid II type glycoproteins, it mainly expresses in the epithelial cell of normal human prostate tissue, but is raised in carcinoma of prostate (comprising metastatic disease).PSMA be with poly-γ glutamic acid folic acid there is reactive unique exopeptidase, PSMA can remove the end of poly-γ paddy acyl group in order.Because PSMA almost in all carcinoma of prostate express and its express bad differentiation, transfer with hormone refractory cancer in improve further, so PSMA is the very noticeable target spot for prostate imaging and treatment.Therefore, research and development and PSMA occur to interact and part with suitable radionuclide can provide the new method be expected to for detecting, treating and monitor carcinoma of prostate.
Radioactivity-the immune conjugate (being called that PROSTASCINT scans) formed by anti-PSMA monoclonal antibody (mAb) 7E11 is just being used to transfer and the recurrence of diagnosing prostate cancer at present.Recently, be combined with the extracellular domain of PSMA and the monoclonal antibody with radionuclide shows accumulates in the PSMA positive prostate tumor model of animal.But use monoclonal antibody carries out diagnosis and lesion detection has been subject to monoclonal antibody infiltrative restriction lower in entity tumor.Therefore, use low-molecular-weight radiopharmaceutical compound to carry out lesion detection and be expected to be developed the potential diagnosis of the radioconjugates of monoclonal antibody as an alternative and the optional manner of radiation treatment.
Radiopharmaceutical selectivity target cancer cell is adopted to there are some problems for imaging or therapeutic purposes.Multiple radionuclide known in the art can be used for the radiotherapy of radiological imaging or cancer, comprises
111in,
90y,
68ga,
177lu,
99mtc,
123i and
131i.Recently, containing being connected to the glutamic acid-carbamide-glutamic acid (GUG) of radionuclide-complex or glutamic acid-some compounds of carbamide-lysine (GUL) recognition element have shown has high-affinity to PSMA.Importantly, the present inventor finds that the affinity of GUL-radionuclide conjugation thing and GUG-radionuclide conjugation thing depends at least partly and GUL or GUG group is connected to the connector of radionuclide complex or the chemical characteristic of interval body and size.
The present invention is conceived to GUL-radioactive complexes or GUG-radioactive complexes, these two kinds of radioactive complexes have one or more than one triazine group optionally replaced, and this group is as the part of connector GUL or GUG group being coupled to radioactive complexes.More specifically, the present invention have studied these structure-function activity based on the connector of triazine, such as, these structure-function activity based on the connector of triazine are studied by the relation between the position of triazine group (such as, piperazinyl-triazine-PAB group) that optionally replaces in the relation between research binding affinity and connector length and binding affinity and connector.And, the invention describes synthesis based on the radiopharmaceutic method of triazine and the method for sign and use GUL-radionuclide of the present invention and GUG-radionuclide conjugation thing Diagnosis and Treat cancer.
Summary of the invention
The present invention relates to the compound of PSMA targeting group and the radionuclide complex of compound of the present invention that have and be connected with radionuclide chelation group.More specifically, technology of the present invention is conceived to synthesis and the application of the synthesis of compound and the radionuclide complex of application and compound of the present invention, and described compound follows following formula: [PSMA identifies motif]-connector-[radionuclide chelation group].As hereinafter further described, compound of the present invention and radionuclide complex thereof comprise the 1,3,5-triazines group in connector.Being incorporated to because it provides three to identify the connection site of motif and radionuclide chelation group and the pharmacokinetic property that has advantage and improve compound of the present invention and radionuclide complex thereof for PSMA of 1,3,5-triazines group.
The present invention also provides the pharmaceutically acceptable preparation of compound of the present invention and radionuclide complex thereof.Described preparation is applicable to treatment various diseases disease, includes but not limited to: carcinoma of prostate, breast carcinoma, carcinoma of the colon and rectum, the brain cancer, pulmonary carcinoma, hepatocarcinoma, carcinoma of endometrium, osteocarcinoma, ovarian cancer, carcinoma of testis, skin carcinoma, cancer of pancreas, uterus carcinoma, cervical cancer, bladder cancer, esophageal carcinoma, gastric cancer, head and neck cancer or renal carcinoma.
Therefore, in one embodiment, the invention provides according to the compound of general formula I and stereoisomer, tautomer, prodrug and pharmaceutically acceptable salt or ester.
In general formula I, A is (CHR
1)
mor C (O) and W is selected from following groups: – C (O) – (CH
2)
p-;-C (O) [-CH
2-CH
2-O]
n-,-[CH
2-CH
2-O]
n-(CH
2)
2-， – C (O)-[CH (R
3)
t]
q-,-(CH
2)
m-O-(CH
2)
n-,-(CH
2)
m-S-(CH
2)
n-,-(CH
2)
m-S (O)-(CH
2)
n-,-(CH
2)
m-S (O)
2-(CH
2)
n-, and-(CH
2)
m-NR
a-(CH
2)
n-.Substituent group Y is selected from: – NH-,-NR
2-, or
and the X in general formula I is selected from: – (C
1-C
10) alkylidene-(C
3-C
10) arlydene ,-(C
3-C
10) arlydene ,-(C
3-C
10) Ya Fangji – (C
1-C
10) alkylidene-, phenylene ， – (C
1-C
10) alkylidene-(C
3-C
10) ring alkylidene ,-(C
3-C
10) ring alkylidene, or-(C
3-C
10) ring Ya Wan Ji – (C
1-C
10) alkylidene-.
R in general formula I
1and R
2can separately be selected from: H ,-(C
1-C
10) alkyl ， – C (O)-(C
1-C
10) alkyl, benzyl ,-(C
3-C
10) cycloalkyl, or-(C
3-C
10) aryl.For the compound of general formula I, R
aand R
bseparately be selected from following groups: H ,-OH ,-(C
1-C
10) alkyl ,-[CH
2-CH
2-O]
n-(CH
2)
2-T ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-Z, benzyl ,-(C
3-C
10) cycloalkyl ,-(C
3-C
10) aryl-(C
1-C
10) alkylidene ,-(C
3-C
10) aryl, halo-(C
1-C
10) alkyl, hydroxyl-(C
1-C
10) alkyl ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-, or R
aand R
band nitrogen bonded thereto together forms (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl, (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl can comprise further and is selected from N, one or more than one hetero atom of S or O.
Z in general formula I is selected from: – OH ,-O (C
1-C
10) alkyl,
further, substituent R
ccan be selected from :-OH ,-O (C
1-C
10) alkyl ,-O benzyl ,-O (C
3-C
10) cycloalkyl ,-O (C
3-C
10) aryl ,-O-(C
1-C
10) alkylidene-(C
3-C
10) aryl, or-O-(C
1-C
10) alkylidene--(C
3-C
10) cycloalkyl.
For the compound of general formula I, R
3be selected from: H, halogen ,-OH ,-NH
2， – (CH
2)
p-COOH ， Huo – (CH
2)
p-NH
2, substituent group T is selected from: – H ， – OH ,-COOH ， Huo – NR
dr
eand R
dand R
eseparately be selected from: H, chemical bond ,-OH ,-(C
1-C
10) alkyl, or-(C
3-C
10) heteroaryl-(C
1-C
10) alkylidene.Subscript m in general formula I, n, p, q, t and r are separately 0,1,2,3,4,5,6,7,8,9 or 10; And group D is selected from:
Any alkyl in general formula I, alkylidene, aryl, arlydene, heteroaryl, heteroarylidene, cycloalkyl, ring alkylidene, Heterocyclylalkyl or heterocycloalkylene group are optionally replaced by 1,2 or 3 substituent groups being selected from following groups, and described group is selected from :-(C
1-C
10) alkyl ,-(C
1-C
10) haloalkyl ,-(C
1-C
10) aminoalkyl ,-(C
1-C
10) alkylidene-COOH ,-(C
1-C
10) hydroxy alkyl ,-OH, halogen ,-NH
2,-COOH ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-X ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-， is with – NR
dr
e.According to these definition, for the compound of general formula I, X is phenylene, r is 1 and D is
The present invention also provides the compound of general formula I I and stereoisomer, tautomer, prodrug and pharmaceutically acceptable salt or ester, and their pharmaceutically acceptable preparations, described preparation is as the therapeutic agent being used for the treatment of the various different morbid states relevant from not controlled cell proliferation.
In general formula I I, A is (CHR
1)
mor C (O) and substituent group W is selected from following groups: – C (O) – (CH
2)
p-;-C (O) [-CH
2-CH
2-O]
n-,-[CH
2-CH
2-O]
n-(CH
2)
2-， – C (O)-[CH (R
3)
t]
q-,-(CH
2)
m-O-(CH
2)
n-,-(CH
2)
m-S-(CH
2)
n-,-(CH
2)
m-S (O)-(CH
2)
n-,-(CH
2)
m-S (O)
2-(CH
2)
n-, and-(CH
2)
m-NR
a-(CH
2)
n-.
Group Y in general formula I I is selected from: – NH-,-NR
2-,
variable R simultaneously
1and R
2separately be selected from: H ,-(C
1-C
10) alkyl ， – C (O)-(C
1-C
10) alkyl, benzyl ,-(C
3-C
10) cycloalkyl, or-(C
3-C
10) aryl.
In general formula I I, R
aand R
bseparately be selected from following groups: H ,-OH ,-(C
1-C
10) alkyl ,-[CH
2-CH
2-O]
n-(CH
2)
2-T ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-Z, benzyl ,-(C
3-C
10) cycloalkyl ,-(C
3-C
10) aryl-(C
1-C
10) alkylidene ,-(C
3-C
10) aryl, halo-(C
1-C
10) alkyl, hydroxyl-(C
1-C
10) alkyl ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-.Alternatively, R
aand R
band nitrogen bonded thereto together forms (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl, (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl can comprise further and is selected from N, one or more than one hetero atom of S or O.
Z in general formula I I is selected from: – OH ,-O (C
1-C
10) alkyl,
and substituent R
cbe selected from :-OH ,-O (C
1-C
10) alkyl ,-O benzyl ,-O (C
3-C
10) cycloalkyl ,-O (C
3-C
10) aryl ,-O-(C
1-C
10) alkylidene--(C
3-C
10) aryl, or-O-(C
1-C
10) alkylidene--(C
3-C
10) cycloalkyl.
For the compound of general formula I I, R
3be selected from: H, halogen ,-OH ,-NH
2， – (CH
2)
p-COOH ， Huo – (CH
2)
p-NH
2, T is selected from: – H ， – OH ,-COOH ， Huo – NR
dr
e, and R
dand R
eseparately be selected from: H, chemical bond ,-OH ,-(C
1-C
10) alkyl, or-(C
3-C
10) heteroaryl-(C
1-C
10) alkylidene.
Any alkyl in general formula I I, alkylidene, aryl, arlydene, heteroaryl, heteroarylidene, cycloalkyl, ring alkylidene, Heterocyclylalkyl or heterocycloalkylene group optionally can be replaced by 1,2 or 3 substituent groups being selected from following groups, and described group is selected from :-(C
1-C
10) alkyl ,-(C
1-C
10) haloalkyl ,-(C
1-C
10) aminoalkyl ,-(C
1-C
10) alkylidene-COOH ,-(C
1-C
10) hydroxy alkyl ,-NH
2,-COOH ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-X ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-He – NR
dr
e, and subscript m, n, p, q, t and x are separately 0,1,2,3,4,5,6,7,8,9 or 10.
For the compound of general formula I I, A is (CH
2)
m, W Shi – C (O) – (CH
2)
p-and Y Shi – NH-or
in one embodiment, A is (CH
2)
2, W is-C (O)-(CH
2)
7-or-C (O)-(CH
2)
10-and Y be
r
aand R
bbe separately hydrogen or methyl and substituent R
cshi – OH.
In one embodiment, R
aand R
band nitrogen bonded thereto together forms (C
3-C
6)-Heterocyclylalkyl, such as, is selected from following group: piperidines, piperazine, morpholine, thiomorpholine, isothiazolidine, isoxazole alkane, pyrrolidine, imidazolidine, Thiazolidine, oxazolidine or 4-(piperidin-4-yl) butanoic acid.
For the compound of some other general formula Is I, R
abe-H and R
bbe
wherein, radicals R
dand R
ebe separately-(C
3-C
10) heteroaryl-(C
1-C
10) alkylidene, such as
Technology of the present invention also comprises the metal complex of the compound comprising radionuclide and general formula I or general formula I I.The radionuclide used is selected from:
111in,
90y,
68ga,
64cu
153gd,
155gd,
157gd,
59fe,
225ac,
212bi,
213bi,
55co,
67cu,
165dy,
166ho,
192ir,
223ra,
186re,
188re,
105rh,
212pb,
213pb,
149tb,
227th,
153sm,
89sr,
117msn,
169yb,
90y,
86y,
89zr and
177lu.
The present invention also provides the radionuclide complex of compound of the pharmaceutically acceptable salt of the compound of general formula I or general formula I I, stereoisomer, tautomer or prodrug and general formula I or general formula I I.
The radionuclide complex of the compound of general formula I or general formula I I and pharmaceutical formulations thereof are for obtaining Radionuclide imaging image or being used for the treatment of various diseases and disease, and described disease or disease include but not limited to: carcinoma of prostate, breast carcinoma, colon cancer, the brain cancer, pulmonary carcinoma, hepatocarcinoma, carcinoma of endometrium, osteocarcinoma, ovarian cancer or renal carcinoma.
In one embodiment, the invention provides and a kind of obtain a kind of method expressing the of prostate specific membrane antigen (PSMA) or the Radionuclide imaging image more than a kind of tissue, described method comprise (a) make a kind of of expression PSMA or more than a kind of tissue with comprise radionuclide and contact with the compound of general formula III or the metal complex of its pharmaceutically acceptable salt or solvate;
And (b) records a kind of or more than a kind of Radionuclide imaging image of tissue.
According to the method, the substituent group G in general formula III is
l is selected from: – NH-(C
1-C
10) alkylidene-， – NH-(C
1-C
10) alkylidene-C (O)-， – C (O)-(C
1-C
10) alkylidene-， – C (O)-(C
1-C
10) alkylidene-C (O)-or-C (O)-(C
1-C
10) alkylidene
and R
aand R
bseparately be selected from: H ,-OH ,-(C
1-C
10) alkyl ,-[CH
2-CH
2-O]
n-(CH
2)
2-T ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-Z, benzyl ,-(C
3-C
10) cycloalkyl ,-(C
3-C
10) aryl-(C
1-C
10) alkylidene ,-(C
3-C
10) aryl, halo-(C
1-C
10) alkyl, hydroxyl-(C
1-C
10) alkyl ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-.
For the compound of some general formula III, R
aand R
b(C is together formed with nitrogen bonded thereto
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl, it can comprise further and is selected from N, one or more than one hetero atom of S or O.
Substituent group Z in general formula III is selected from: – OH ,-O (C
1-C
10) alkyl,
substituent R
dand R
eseparately be selected from: H, chemical bond ,-OH ,-(C
1-C
10) alkyl, or-(C
3-C
10) heteroaryl-(C
1-C
10) alkylidene, and subscript n be selected from 0,1,2,3,4,5,6,7,8,9 or 10 integer.
According to a kind of embodiment, as mentioned above, the invention provides and be used for the treatment of as therapeutic agent the radionuclide complex that diagnosis suffers from the general formula I of the patient of cancer (such as carcinoma of prostate) or the compound of general formula I I.Treatment according to method of the present invention has come by the prostate specific membrane antigen (PSMA) for the treatment of effective dose is delivered medicine to patient in conjunction with complex, described prostate specific membrane antigen (PSMA) comprises triazine connector in conjunction with complex, and relative to not expressing the tissue of PSMA, can be trapped in the tumor tissues of expressing PSMA and continuing longer interval.
Accompanying drawing explanation
Fig. 1 illustrates according to the present invention (2S)-2-(3-(1-carboxyl-5-(11-(4-(4-((2-(2-(2-Carboxyethoxy) ethyoxyl) ethyl) is amino)-6-((4-((1 in LNCap xenograft mouse body, 4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid
177tissue biological's distribution of Lu complex.
Fig. 2 illustrates according to the present invention (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1 in LNCap xenograft mouse body, 4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid
177tissue biological's distribution of Lu complex.
Fig. 3 illustrates (21S, the 25S)-8,15 being used as the contrast in LNCap xenograft mouse body according to the present invention, 23-tri-oxygen-1-(4-((Isosorbide-5-Nitrae, 7,10-tetra-(carboxymethyl group)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-2-base) methyl) pentyl amino)-1 sulfo--2,7,16,22,24-pentaaza heptacosane-21,25,27-is tricarboxylic
177tissue biological's distribution of Lu complex.
Fig. 4 illustrates according to the present invention (2S)-2-in LNCap xenograft mouse body (3-((1S)-1-carboxyl-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid
177tissue biological's distribution of Lu complex.
Fig. 5 illustrates (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid
177lNCaP tumor growth is suppressed in Lu complexation object.
Fig. 6 illustrates (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid
68ga complex delivers medicine to the Radionuclide imaging image that the patient that suffers from carcinoma of prostate obtains.
Detailed description of the invention
There are two radiomimetic drugs in this area: (i) accurately determines chorologic by blood flow, or accurately determine those radiopharmaceutical that the are chorologic and High Capacity System of targeting such as glomerulus filtration, phagocytosis, hepatocyte removing and bone resorption and so on by perfusion; And (ii) determines those radiopharmaceutical of distribution by enzyme-specific or receptors bind interaction, described interaction is low capacity site.Belong to Equations of The Second Kind according to the radiopharmaceutical of general formula I or general formula I I and by use the connector with triazine group by radionuclide co-ordination complex with to psma protein, there is optionally bioactive molecule coupling and synthesize.
Term " connector ", " interval body ", " connector group " or " interval body group " exchange use in this article, and refer to the group be connected across between two other groups identified or the group separated by described two other groups identified.Connector or interval body can be chemical bond, organic group or atom or inorganic group or atom.
In some embodiments, described connector or interval body are the (C optionally replaced
1-C
15) alkylidene, (C
2-C
15) alkenylene, (C
2-C
15) alkynylene group ， – C (O)-(C
1-C
15) alkylidene-,-C (O)-(C
3-C
15) arlydene-(C
1-C
15) alkylidene-,-W-Y-(C
3-C
15) heteroarylidene-NH-X-(CH
2)
r-， Huo – C (O)-(C
1-C
15) alkylidene-Y-(C
3-C
15) heteroarylidene-NH-X-, wherein, variable " W ", " X " and " Y " further describes hereinafter.Exemplary substituent group includes but not limited to: carboxyl, carboxylate, hydroxyl and amino (NR
ar
b) group.For some embodiments, (the C in above-mentioned connector
1-C
15) alkylidene can by (C
1-C
15) polyhydric alcohol substitute, described (C
1-C
15) polyhydric alcohols is as Polyethylene Glycol (PEG) group.Exemplary connector or interval body illustrate in description and embodiment, but are not limited thereto.
Conveniently, some terms used in this definition this paper and accompanying claim.
" about " used herein can be understood by those of ordinary skill in the art and based on its context of co-text that uses can change to a certain extent.If employ the unclear term of those of ordinary skill in the art's implication, so in the context of co-text using " about ", " about " refers to positive and negative 10% of particular term.
Illustrate that the embodiment of description can not exist any key element or multiple key element herein, suitably implement under there is not the condition of certain restriction or multiple restriction, it is specifically open in this article.Therefore, can read that such as term " comprises " widely, " comprising ", " containing " etc., and unrestricted.In addition; term used herein and expression formula are used as descriptive term; and it is unrestricted; be not intended to get rid of shown and described feature or its part any equivalent when using these terms and expression formula; but should be understood that, various different change may be produced in the scope of the technical scheme of application claims protection.In addition, phrase " substantially by ... form " can be understood as that and comprise concrete those key elements of recording and do not affect the basic feature of technical scheme required for protection and those extra key elements of new feature in essence.Phrase " by ... form " get rid of any key element not having to illustrate.
In the context describing key element (especially in accompanying claims), use term " a ", " an " and " the " and the similar thing that refers to may be interpreted as covering odd number and plural form, unless separately had other to illustrate or had obvious contradiction in context herein.
Term used herein " lipophilic group " and " lipophilic moieties " refer to relative to polarity or aqueous environments, have the group of higher affinity, part or substituent group to nonpolar or nonaqueous environment.Such as, Merriam Webster online dictionary definition " lipotropy " is " having affinity to lipid (such as fat) ".Exemplary lipophilic moieties comprises aliphatic hydrocarbon free radical (such as, alkyl diradical), aromatic hydrocarbon free radical and long acyl free radical; They all have the affinity increased along with the increase of composition carbon number.Generally, in standard Octanol/water Partition Coefficients determination code, lipophilic moieties is added in specific compound and can increase the affinity of compound to capryl alcohol; This code can be used for relative hydrophobicity (lipotropy) and the hydrophilic of measuring compound.
Term " part " refers to and with another species, interactional species occurs in some manner.In one embodiment, part can be lewis base, and this lewis base can form lewis acidic coordinate bond.In other embodiments, part is organic species normally, and itself and metal ion form co-ordination complex.In biochemistry and pharmacology, part forms the material (normally micromolecule) of complex for biological object.From in the narrow sense, part is signal Triggering molecules, and it is bonded to the site on target protein.Described in combination with intermolecular force occur, described intermolecular force such as, ionic bond, hydrogen bond and Van der Waals force.
Term " chelating agen " refers to molecule, is generally organic molecule, and normally lewis base, and described chelating agen has two or can supply the unshared electron pair of metal ion more than two.Described metal ion usually and two of chelating agen or more than two electron pair coordinations.Term " bidentate chelating agen ", " three tooth chelating agen " and " four tooth chelating agen " are known in the art and refer to the chelating agen respectively with two, three and four electron pairs, and described electron pair can be easy to supply the metal ion to chelating agen coordination simultaneously.Usually, electron pair and the single metal ion of chelating agen form coordinate bond, but in some embodiments, chelating agen can form coordinate bond with more than one metal ion, may have multiple coordination mode.
Term " coordination " refers to the interaction of a polyelectron to donor and a metal ion generation coordination bonding (coordination).
Term radionuclide refers to the atom with unstable nucleic, and described unstable nucleic is the nucleic characterized by excessive power, and described excessive power can pass to the new radioactive grain of generation or the electronics of atom in atomic nucleus.Radionuclide can experience cooling and in process of radioactive decay, radiate subatomic ionic particles.Exemplary subatomic ionic particles is α-granule, β-granule and γ-granule, but is not limited thereto.Exemplary radionuclide includes but not limited to the radioisotopic element belonging to group of the lanthanides, actinium series and transition metal.Exemplary radionuclide can include but not limited to:
111in,
90y,
68ga,
64cu
153gd,
155gd,
157gd,
59fe,
225ac,
212bi,
213bi,
55co,
67cu,
165dy,
166ho,
192ir,
223ra,
186re,
188re,
105rh,
212pb,
213pb,
149tb,
227th,
153sm,
89sr,
117msn,
169yb,
90y,
86y,
89zr and
177lu.But term is not limited to this four kinds of radionuclides.
Fmoc is the abbreviation of chemical group fluorenylmethoxycarbonyl groups.
The rational benefit/risk ratio that phrase used herein " effective dose " or " treatment effective dose " refer to be applied to any medical therapy effectively produces compound, the material of the therapeutical effect that some are expected or comprises the compositions of compound of the present invention or the amount of other active component at least cell subsets of animal.The treatment effective dose of compound of the present invention refers to the amount of independent therapeutic agent, or the amount of the therapeutic agent of combining with other treatment agent, and this treatment effective dose is in treatment or provide treatment benefit in preventing disease.Can comprise with the term of compound conbined usage of the present invention and improve general curative effect, alleviate or avoid the symptom of disease or the cause of disease or improve the curative effect of another therapeutic agent or the synergistic amount with another therapeutic agent.
Term used herein " treatment (treating or treatment) " is intended to comprise diagnosis, prevention, treatment and cure.The patient accepting this treatment is other mammals of any animal (comprising primate, especially the mankind) and such as horse, cattle, the pig and sheep and so on having this to need; And general poultry and house pet.
Phrase used herein " pharmaceutically acceptable " refers to and within the scope of sufficient medical judgment, to be applicable to contact human body and animal body tissue and can not to produce too much toxicity, stimulation, anaphylaxis or other problems or complication, those compounds, material, compositions and/or the dosage form suitable with rational benefit/risk ratio.
Phrase used herein " pharmaceutically acceptable carrier " refers to relate to and target compound is carried or be delivered to the pharmaceutically acceptable material of a part for another organ or health, compositions or supporting agent from a part for an organ or health, such as, liquid or solid filler, diluent, excipient or solvent encapsulating substance.Often kind of carrier must be compatible with other compositions of preparation and in the meaning that can not be harmful to patient " acceptable ".Some examples that can be used as the material of pharmaceutically acceptable carrier comprise: (1) saccharide, such as, and lactose, dextrose plus saccharose; (2) starch, such as, corn starch and potato starch; (3) cellulose and its derivates, such as, sodium carboxymethyl cellulose, ethyl cellulose and cellulose ethanoate; (4) powdered tragacanth; (5) Fructus Hordei Germinatus; (6) gelatin; (7) Talcum; (8) excipient, such as, cocoa butter and suppository wax; (9) oils, such as, Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil; (10) glycol, such as, propylene glycol; (11) polyhydric alcohol; Such as, glycerol, sorbitol, mannitol and Polyethylene Glycol; (12) esters, such as, ethyl oleate and ethyl laurate; (13) agar; (14) buffer agent, such as, magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) apirogen water; (17) isotonic saline solution; (18) Ringer's mixture; (19) ethanol; (20) pH buffer solution; (21) polyester, Merlon and/or condensing model; And other non-toxic compatible materials that (22) use in pharmaceutical preparation.
" pharmaceutically acceptable salt " is the pharmaceutically acceptable acylate of compound of the present invention or organic alkali salt or inorganic acid salt or inorganic base salts.Representational pharmaceutically acceptable salt comprises, such as, alkali metal salt, alkali salt, ammonium salt, can be water-soluble and can not be water-soluble salt, such as, acetate, amsonate (4,4-diamino-stilbene-2,2-disulfonate), benzene sulfonate, benzoate, bicarbonate, disulfate, biatrate, borate, bromide, butyrate, calcium, edetic acid calcium salt, d-camphorsulfonic acid salt, carbonate, chloride, citrate, Clavulanate, dihydrochloride, edetate, two esilates, estolate (estolate), esilate, fumarate, gluceptate, gluconate, glutamate, Glu, to hydroxyl acetylamino phenyl-arsonate (glycollylarsanilate), hexafluorophosphate, hexyl resorcin salt (hexylresorcinate), Hai Baming (hydrabamine), hydrobromate, hydrochlorate, hydroxynaphthoate, iodide, isothiuronium salts, lactate, lactobionate, month silicate, malate, maleate, mandelate, mesylate, MB, methyl nitrate, Methylsulfate, mucate, naphthalene sulfonate, nitrate, N-methyl glucose osamine ammonium salt, 3-hydroxy-2-naphthoic acid salt, oleate, oxalates, palmitate, embonate (1,1-methylene-bis--2-hydroxyl-3-naphthoate, einbonate), pantothenate, phosphate/Diphosphonate, picrate, Polygalacturonate, propionate, tosilate, Salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, suramin hydrochlorate (suramate), tannate, tartrate, teoclate, toluene fulfonate, triethiodide compound and valerate.Pharmaceutically acceptable salt can have more than one charged atom in its structure.In this case, described pharmaceutically acceptable salt can have multiple equilibrium ion.Therefore, pharmaceutically acceptable salt can have one or more than one charged atom and/or one or more than one equilibrium ion.
Phrase used herein " parenteral " and " with parenteral mode administration " refer to be different from Parenteral administration and topical mode of administration, it passes through drug administration by injection usually, and include but not limited to: intravenous injection and infusion, intramuscular injection and infusion, intra-arterial injection and infusion, intrathecal injection and infusion, intracapsular injection and infusion, injection and infusion in frame, intracardiac injection and infusion, intradermal and infusion, peritoneal injection and infusion, through trachea injection and infusion, subcutaneous injection and infusion, epidermis hemostasis and infusion, intra-articular injection and infusion, capsule hemostasis and infusion, arachnoidea hemostasis and infusion, intraspinal injection and infusion and breastbone inner injection and infusion.
Phrase used herein " Formulations for systemic administration ", " the mode administration with whole body ", " peripherally administered " and " with periphery mode administration " refer to be different from directly deliver medicine to central nervous system mode to drug compound, medicine or other materials, enter entire patient's system to make described compound, medicine or other materials and carry out metabolism and other similar procedure thus, such as, subcutaneous administration.
" patient " comprises animal, such as, and the mankind, cattle, horse, sheep, lamb, pig, chicken, turkey, Carnis Coturnicis japonicae, cat, Canis familiaris L., mice, rat, rabbit or Cavia porcellus.Animal can be the mammal of such as non-human primate and primates (such as, monkey and the mankind) and so on.In one embodiment, patient is the mankind, such as, and human infant, child, teenager or adult.
Term " prodrug " refers to the precursor of medicine, and this precursor must experience chemical conversion by metabolic process and become the compound of active pharmacological reagent subsequently after delivering medicine to patient.Exemplary prodrug according to the compound of general formula I is esters, preferred alkyl esters or fatty acid ester.
Term " hetero atom " refers to the atom of any element being different from carbon or hydrogen.Exemplary hetero atom comprises boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
In general, " replacement " refers to that, in the alkyl hereafter defined, alkylidene, thiazolinyl, alkenylene, alkynyl, alkynylene, aryl, arlydene, cycloalkyl or ring alkylidene group, one or more than one chemical bond of wherein comprised hydrogen atom is substituted by the chemical bond of non-hydrogen atom or non-carbon.The group that one or more than one chemical bond that the group replaced also comprises wherein carbon atom or hydrogen atom is substituted by one or more than one chemical bond heteroatomic, described chemical bond comprises double bond or triple bond.Therefore, the group of replacement can be replaced by one or more than one substituent group, except as otherwise noted.In some embodiments, the group of replacement is replaced by 1,2,3,4,5 or 6 substituent groups.Substituent example comprises: halogen (that is, F, Cl, Br and I), hydroxyl; Alkoxyl, alkene oxygen base, alkynyloxy group, aryloxy group, aralkoxy, heterocyclic oxy group and heterocyclylalkoxy groups; Carbonyl (oxygen); Carboxyl; Ester; Carbamate; Oxime; Hydroxylamine; Alkoxyamine; Aralkoxy amine; Sulfur alcohol; Sulfide; Sulfoxide; Sulfone class; Sulfonyl; Sulfonamide; Amine; N-oxide; Hydrazine; Hydrazides; Hydrazone; Azide; Amide; Carbamide; Amidine; Guanidine; Enamine; Acid imide; Isocyanates; Different thiocyanic ester; Cyanate; Thiocyanic ester; Imines; Nitro; Nitrile (that is, CN), haloalkyl, aminoalkyl, hydroxy alkyl, cycloalkyl, etc.
Alkyl comprises straight chain and branched alkyl, and this alkyl has 1 to 12 carbon atom, usually has 1 to 10 carbon atom, and at some embodiments, this alkyl has 1 to 8,1 to 6 or 1 to 4 carbon atom.The example of straight chained alkyl comprises following group, such as, and methyl, ethyl, n-propyl group, n-butyl, n-amyl group, n-hexyl, n-heptyl and n-octyl group.The example of branched alkyl includes, but are not limited to: isopropyl, isobutyl group, sec-butyl, the tert-butyl group, neopentyl, isopentyl and 2,2-dimethyl propyl group.Alkyl group can be replacement or unsubstituted.Carbon number unless otherwise, " low alkyl group " refers to alkyl as defined above, but in its framing structure, have 1 to about 10 carbon atom, have 1 to about 6 carbon atom alternatively.Similarly, " low-grade alkenyl " and " low-grade alkynyl " has similar chain length.
Term " alkylidene " and " alkylidene of replacement " refer to the alkyl of divalent alkyl and bivalent substituted respectively.The example of alkylidene includes but not limited to: ethylidene (-CH2-CH2-)." alkylidene optionally replaced " refers to the alkylidene of alkylidene or replacement.
Term " alkyl-carbonyl " or " alkylenecarbonyl " refer to wherein C
1-C
8at least one in alkyl methylene is by C (O) group Ti Dai – (C
1-C
8) alkyl-C (O)-or-C (O) – (C
1-C
8) alkyl-radical.Representational example includes but not limited to: acetyl group, propiono and CH
3(CH
2)
2c (O)-group ， Huo – CH
2(CH
2)
2c (O)-.
Term " cyclic alkyl " or " cycloalkyl " refer to have 3 to 14 carbon atoms but the non-aromatic cyclic alkyl group without the saturated of ring hetero atom or fractional saturation, and this cyclic alkyl radical has single ring or multiple ring, comprise that condense with loop systems that is bridge joint.Group of naphthene base can be replacement or unsubstituted.Cycloalkyl or cyclic alkyl radical comprise in ring and have 3 monocycle alkyl to 14 carbon atoms, bicyclic alkyl or tricyclic alkyl, or in some embodiments, described monocycle alkyl, bicyclic alkyl or tricyclic alkyl have 3 to 12 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms or 3 to 4,5,6 or 7 carbon atoms.Exemplary monocyclic cycloalkyl includes but not limited to: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and ring octyl groups.The cycloalkyl that bicyclic system and three-loop system comprise bridge joint and the ring condensed, such as, but not limited to: dicyclo [2.1.1] hexane, adamantyl, decahydro naphthyl, etc.
" ring alkylidene " is the non-aromatic group of naphthene base having 3 to 14 carbon atoms and do not have the saturated or fractional saturation of the bivalence of ring hetero atom.
Thiazolinyl comprises straight chain as defined above and side chain and group of naphthene base, except there is at least one double bond between two carbon atoms.Therefore, in some embodiments, alkenyl group has 2 to about 12 carbon atoms, in other embodiments, has 2 to 10 carbon atoms, in other embodiments, has 2 to 8 carbon atoms.Example includes but not limited to: vinyl, pi-allyl ,-CH=CH (CH
3) ,-CH=C (CH
3)
2,-C (CH
3)=CH
2,-C (CH
3)=CH (CH
3) ,-C (CH
2cH
3)=CH
2, cyclohexenyl group, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl, etc.Alkenyl group can be substituted or unsubstituted.The alkenyl group of representational replacement can be mono-substituted or more than once replacing, such as but not limited to: mono-substituted, disubstituted or trisubstituted by substituent group (those such as listed above substituent groups).
Term " alkenylene " refers to bivalence thiazolinyl.The example of alkenylene includes but not limited to: ethenylidene (-CH=CH-) and stereoisomer thereof and configurational isomers." alkenylene of replacement " refers to the thiazolinyl of bivalent substituted." alkenylene optionally replaced " refers to the alkenylene of alkenylene or replacement.
" alkynes " or " alkynyl " refers to the straight chain and side chain unsaturated hydrocarbons with carbon number and at least one triple bond of specifying.(C
2-C
8) example of alkynyl group includes but not limited to: acetylene, propine, ethyl acetylene, 2-butyne, 1-pentyne, valerylene, 1-hexin, 2-hexin, 3-hexin, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne and 4-octyne.Alkynyl group can be unsubstituted or optionally be replaced by one or more than one substituent group hereafter defined.
Term " alkynylene " refers to divalent alkynyl radical.The example of alkynylene includes but not limited to: second alkynylene, the third alkynylene." alkynylene of replacement " refers to the alkynyl of bivalent substituted.
Aromatic yl group does not comprise heteroatomic cyclic aromatic hydrocarbon.Aromatic yl group comprises monocycle, dicyclo and multi-loop system.Therefore, aromatic yl group includes but not limited to: phenyl, Flos Chrysanthemi cyclic group (azulenyl) trialkenyl (heptalenyl) between heptan, biphenylene (biphenylenyl), bicyclopentadiene phenyl (indacenyl), fluorenyl, phenanthryl (phenanthrenyl), triphenylenyl, pyrenyl, naphthacenyl (naphthacenyl),
base (chrysenyl), xenyl, anthryl, indenyl, indanyl, pentalene base (pentalenyl) and naphthyl.In some embodiments, aromatic yl group comprises 6 to 14 carbon atoms, and in other embodiments, aromatic yl group comprises 3 to 12 or even 3 to 10 carbon atoms at the loop section of group.Aromatic yl group comprises replacement with unsubstituted aromatic yl group.The aromatic yl group replaced can be mono-substituted or more than once replacing.Such as, mono-substituted aromatic yl group includes but not limited to: can be substituted that base (those substituent groups such as enumerated) replaces above 2,3-, 4-, 5-, or the phenyl or naphthyl group that 6-replaces.
" arlydene " refers to divalent aryl, and " arlydene of replacement " refers to the aryl of bivalent substituted." arlydene optionally replaced " refers to the arlydene of arlydene or replacement.Exemplary arylene group is phenylene.
" Heterocyclylalkyl " refers to have 5 saturated or unsaturated non-aromatic monocyclic to 14 atoms, dicyclo, three rings or multi-ring member ring systems, and wherein, 1 in ring to 3 carbon atoms are substituted by O, S or N hetero atom.Heterocyclylalkyl optionally with 5 yuan to 6 yuan benzos or heteroaryl-condensed and comprise S or N of oxidation, such as, the N-oxide of sulfinyl, sulfonyl and three ring nitrogen.The junction point of heterocycloalkyl ring is carbon or hetero atom, to maintain stable ring.The example of Heterocyclylalkyl includes but not limited to: morpholinyl, tetrahydrofuran base, dihydropyridine base, piperidyl, pyrrolidinyl, piperazinyl, dihydro benzo furyl and indolinyl.
" Heterocyclylalkyl optionally replaced " refers to by 1 to 3 substituent group (such as, 1,2 or 3 substituent groups) Heterocyclylalkyl that replaces, this Heterocyclylalkyl is connected to produce stable compound on any spendable atom, and wherein, substituent group is as herein described.
" cycloalkyl " refer to monocycle, dicyclo, three rings or multi-ring, 3 yuan to 14 ring system, this member ring systems is saturated, undersaturated or aromatic.Group of naphthene base connects by any atom.Cycloalkyl also relates to the ring condensed, and wherein, cycloalkyl and aryl mentioned above or heteroaryl ring condense.The representative example of cycloalkyl includes but not limited to: cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.Group of naphthene base can be unsubstituted or optionally be replaced by one or more than one hereafter described substituent group.
Term " ring alkylidene " refers to divalent cycloalkyl.Term " the ring alkylidene optionally replaced " refers to by 1 to 3 substituent group (such as, 1,2 or 3 substituent groups) the ring alkylidene that replaces, this ring alkylidene is connected on any spendable atom to produce stable compound, wherein, described substituent group is as herein described.
Term " (C
3-C
14) aryl-(C
1-C
6) alkylidene " refer to divalent alkyl, wherein, C
1-C
6one or more than one hydrogen atom in alkylidene group is by (C
3-C
14) aromatic yl group substitute.(C
3-C
14) aryl-(C
1-C
6) example of alkylidene includes but not limited to: 1-phenyl butylidene, phenyl-2-butylidene, 1-phenyl-2-methyl propylene, phenylmethylene, phenylpropylene and naphthyl ethylidene.
Term " (C
1-C
10) alkylidene-(C
3-C
14) arlydene " refer to divalent arylen, wherein, C
3-C
14one or more than one hydrogen atom in arlydene is by (C
1-C
10) alkyl group substitutes and in the hydrogen of wherein alkyl group one is substituted by another group.(C
1-C
10) alkylidene-(C
3-C
14) example of arlydene includes but not limited to: butylidene-4-phenylene, propylidene-2-phenylene and 1-[2-methyl propylene] phenylene.
Term " (C
3-C
14) arlydene-(C
1-C
10) alkylidene " refer to divalent alkyl, wherein, C
1-C
10one or more than one hydrogen atom in alkylidene is by bivalence (C
3-C
14) arylene group substitute.Exemplary (C
3-C
14) arlydene-(C
1-C
10) alkylidene group includes but not limited to: phenylene-4-butylidene, phenylene-2-butylidene and phenylene-1-[2-methyl propylene].
Aralkyl be the hydrogen of wherein alkyl or carbon bond by the chemical bond of above-mentioned aryl substitute above the alkyl group that defines.In some embodiments, aralkyl comprises 7 to 20 carbon atoms, 7 to 14 carbon atoms or 7 to 10 carbon atoms.
" heterocyclic radical " or " Heterocyclylalkyl " refers to the non-aromatic cycle compound comprising 3 or more ring memberses, wherein, one or more than one ring carbon atom is substituted by hetero atom, and described hetero atom is such as but not limited to N, O and S.In some embodiments, heterocyclic group comprises 3 to 20 ring memberses, and other this groups have 3 to 6,3 to 10,3 to 12 or 3 to 15 ring memberses.Heterocyclic group comprises undersaturated, fractional saturation with saturated member ring systems, such as, and imidazole radicals, imidazolinyl and imidazolidinyl.Heterocyclic group can be replacement or unsubstituted.Heterocyclic group includes but not limited to: '-aziridino, azelidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydro-thienyl, tetrahydrofuran base, di azoly, furyl, thienyl, pyrrole radicals, pyrrolinyl, imidazole radicals, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl group, oxadiazoles base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, THP trtrahydropyranyl, tetrahydrochysene thiopyranyl, thioxane (oxathiane), dioxy base (dioxyl), dithiane base (dithianyl), pyranose, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, triazine radical, dihydropyridine base, dihydro dithiins base (dihydrodithiinyl), dihydro two sulfinyl (dihydrodithionyl), equal piperazinyl (homoopiperazinyl), quininuclidinyl, indyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridinyl), indazolyl, indolizine base (indolizinyl), benzotriazole base, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzo oxadiazoles base, benzoxazinyl-, benzo dithiins base, thia cyclohexadienyl disliked by benzo, benzothiazine base, benzoxazolyl, benzothiazolyl, diazosulfide base, benzo [1,3] di azoly, Pyrazolopyridine base, imidazopyridyl (azabenzimidazoles base), Triazolopyridine base, isoxazole pyridine radicals, purine radicals, xanthinyl, adenyl, guanyl-, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl, quinazolyl, cinnolines base, phthalazinyl, naphthyridinyl, petrin base, thianaphthenyl, dihydrobenzo thiazinyl, dihydro benzo furyl, indolinyl, dihydrobenzo dioxin base, tetrahydro indole base, tetrahydrochysene indazole base, Tetrahydrobenzimidazderivative base, tetrahydro benzo triazolyl, nafoxidine pyridine radicals, tetrahydro-pyrazole pyridine radicals, imidazolidine pyridine radicals, tetrahydrochysene Triazolopyridine base and tetrahydric quinoline group.Heterocyclic group can be substituted or unsubstituted.The heterocyclic group of representational replacement can be mono-substituted or be replaced such as but not limited to pyridine radicals or morpholinyl more than once, the heterocyclic group replaced be replaced by various different substituent group (such as, above listed those substituent groups) 2-, 3-replaces, 4-replaces, 5-replaces or 6-replaces or disubstituted.
Heteroaryl groups comprises 5 or aromatic ring compound more than 5 ring memberses, and wherein, one or more than one ring carbon atom is substituted by the hetero atom such as but not limited to N, O and S.Heteroaryl groups can be replacement or unsubstituted.Heteroaryl groups includes but not limited to following groups, such as: pyrrole radicals, pyrazolyl, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, thiazolyl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, thienyl, benzothienyl, furyl, benzofuranyl, indyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridyl (azabenzimidazoles base), Pyrazolopyridine base, Triazolopyridine base, benzotriazole base, benzoxazolyl, benzothiazolyl, diazosulfide base, imidazopyridyl, isoxazole pyridine radicals, thianaphthenyl, purine radicals, xanthinyl, adenyl, guanyl-, quinolyl, isoquinolyl, tetrahydro isoquinolyl, quinoxalinyl and quinazolyl.
Term " alkoxyl " refers to-O-alkyl group having and specify carbon number.Such as, (C
1-C
10) alkoxy base comprises-O-methyl (methoxyl group),-O-ethyl (ethyoxyl),-O-propyl group (propoxyl group),-O-isopropyl (isopropoxy),-O-butyl (butoxy),-O-sec-butyl (sec-butoxy),-O-the tert-butyl group (tert-butoxy),-O-amyl group (amoxy),-O-isopentyl (isoamoxy),-O-neopentyl (neopentyl oxygen) ,-O-hexyl (hexyloxy) ,-O-isohesyl (different hexyloxy) and the new hexyl of-O-(new hexyloxy).The example of cycloalkoxy groups includes but not limited to: ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, etc.Alkoxy base can be substituted or unsubstituted.
Term " carbocyclic ring " refers to that wherein each annular atoms is aromatic series or the non-aromatic ring of carbon.
Term " nitro " refers to-NO
2.
Term " halogen " is known in the art and refers to-F ,-Cl ,-Br Huo – I; Term " sulfydryl " is known in the art and refers to-SH; Term " hydroxyl " refers to-OH; And term " sulfonyl " is known in the art and refers to "-SO
2-"." halogenide " refers to the anion of the correspondence of halogen, the definition that " Pseudohalides " has " Advanced Inorganic Chemistry (Cotton and Wilkinson edits) " cited by the 560th page.
Term " amine or amino " refers to-NR
dr
egroup, wherein, R
dand R
eseparately refer to hydrogen, (C
1-C
8) alkyl, aryl, heteroaryl and Heterocyclylalkyl.Work as R
dand R
ewhen being connected to identical nitrogen-atoms, they can combine formation 5 yuan, 6 yuan or 7 rings with nitrogen-atoms.Such as ,-NR
dr
erefer to and comprise 1-pyrrolidinyl, pyridine radicals or 4-morpholine basic ring.
Term " amide groups " is the carbonyl as amino replacement known in the art and comprises can by general formula-C (O) NR
dr
ethe group that group represents, wherein, R
dand R
eas defined above.
Term " nitrile or cyano group " is used interchangeably and refers to-CN group, and this group bonding is to the carbon atom of heteroaryl ring, aryl rings and heterocycloalkyl ring.
Term " aminoalkyl " refers to (C
1-C
10) one or more than one hydrogen atom in alkyl group is by NR
dr
e(the C that group substitutes
1-C
10) alkyl group, wherein, R
dand R
ecan be identical or different, such as, R
dand R
eseparately refer to hydrogen, (C
1-C
8) alkyl, aryl, heteroaryl, Heterocyclylalkyl, (C
1-C
8) haloalkyl and (C
1-C
10) hydroxyalkyl groups.The example of aminoalkyl groups includes but not limited to: amino methyl, amino-ethyl, 4-aminobutyl and 3-aminobutyl.
Term " halogenated alkoxy " refers to-O-(C
1-C
8)-O-(the C that substituted by halogen atom of one or more than one hydrogen atom in alkyl group
1-C
8) alkyl group, described halogen atom can be identical or can be different.The example of halogenated alkyl group includes but not limited to: difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxies, 4-chlorine butoxy, 3-bromine propoxyl group, pentachloro-ethyoxyl and the bromo-2-chloroethoxy of the fluoro-2-of 1,1,1-tri-.
Term " hydroxy alkyl " refers to one or more than one alkyl group with appointment carbon number substituted by-OH group in the hydrogen atom of wherein alkyl group.The example of hydroxyalkyl groups includes but not limited to :-CH
2oH ,-CH
2cH
2oH ,-CH
2cH
2cH
2oH ,-CH
2cH
2cH
2cH
2oH ,-CH
2cH
2cH
2cH
2cH
2oH ,-CH
2cH
2cH
2cH
2cH
2cH
2oH and their branched form.
" hydroxyl (hydroxyl or hydroxy) " refers to-OH group.
Term " carboxyl " and " carboxylate " comprise some groups that can be represented by following general formula:
Wherein, E is chemical bond or represents O or S, and R
fand R
f 'be H, alkyl, thiazolinyl, aryl or its pharmaceutically acceptable salt independently.When E is O, and R
fwhen being as defined above, this group is called as carboxyl in this article, and, specifically, work as R
fhydrogen, above-mentioned general formula representative " carboxylic acid ".In general, when clearly showing to substitute oxygen by sulfur, general formula represents " thiocarbonyl " group.
Substituent group-CO
2h can be substituted by bioisostere alternative, described bioisostere alternative such as following groups:
Wherein, R has and R ' defined herein and R " identical definition.See, such as, the 203rd page in THEPRACTICE OF MEDICINAL CHEMISTRY (academic press: New York, 1996).
Term " alkoxyl (alkoxyl or alkoxy) " refers to the alkyl as defined above with connected oxygen-derived free radicals.Representational alkoxyl comprises methoxyl group, ethyoxyl, propoxyl group, butoxy, tert-butoxy, etc." ether " is by two covalently bound hydrocarbon of oxygen." ether " also comprises the polyethers that wherein can there is more than one ether group or ether connection in given group." ether " also comprises cyclic ethers and crown ether, and wherein, ether connects and is present in cyclic group.
Term " (C
5-C
14) aryl-(C
1-C
10) alkylidene " refer to wherein C
1-C
10one or more than one hydrogen atom in alkylidene is by (C
3-C
14) aryl substitute divalent alkyl.(C
3-C
14) aryl-(C
1-C
10) example of alkylidene includes but not limited to: 1-phenyl butylidene, phenyl-2-butylidene, 1-phenyl-2-methyl propylene, phenylmethylene, phenylpropylene and naphthyl ethylidene.
Term " (C
5-C
14) heteroaryl-(C
1-C
10) alkylidene " refer to wherein C
1-C
10one or more than one hydrogen atom in alkylidene is by (C
3-C
14) heteroaryl substitute divalent alkyl.(C
3-C
14) heteroaryl-(C
1-C
10) example of alkylidene includes but not limited to: 1-pyridine radicals butylidene, quinolyl-2-butylidene and 1-pyridine radicals-2-methyl propylene.
Term "-(C
5-C
14) heteroarylidene-(C
1-C
10) alkylidene " refer to wherein C
1-C
10one or more than one hydrogen atom in alkylidene is by (C
3-C
14) heteroaryl substitutes and or (C wherein in hydrogen atom
3-C
14) heteroaryl hetero atom in one with another group (such as, (C
1-C
10) alkyl) divalent alkyl of bonding.
" benzyl " is
and term " benzylidene " refers to bivalence benzyl group, it is by following representation:
Halogen refers to chlorine, bromine, fluorine or iodine.
The definition of each expression formula (such as alkyl, m, n, etc.), when occurring in any structure more than one time, is intended to the definition independent of its other positions in identical structure.
Term trifyl, tosyl, mesyl and perfluorobutanesulfonyl refer to trifluoromethanesulphonyl respectively, p-toluenesulfonyl, mesyl and perfluoro fourth sulfonyl.Term triflate, tosylate, methanesulfonates and perfluor butanesulfonate are known in the art and refer to trifluoro acute pyogenic infection of nails sulphonic acid ester respectively, p-toluenesulfonic esters, methanesulfonates and perfluoro fourth sulphonic acid ester and the molecule containing these groups.Abbreviation Me, Et, Ph, Tf, Nf, Ts and Ms represent methyl, ethyl, phenyl, trifyl, perfluorobutanesulfonyl, p-toluenesulfonyl and mesyl respectively.The more comprehensive abbreviated list used by the organic chemist in those of ordinary skill in the art was listed in the first phase of each volume of Journal ofOrganic Chemistry, and this list normally title is the form of standardized abbreviations list.
Some compounds comprised in compositions can be present in particular geometric isomer or stereoisomer form.In addition, compound can also be optically active.Compound also can comprise cis-trans-isomer, R-and S-enantiomer, diastereomer, (D)-isomer, (L)-isomer and racemic mixture thereof, and their other mixture.Other asymmetric c atoms can be present in the substituent group of such as alkyl and so on.Such as, if the given enantiomer of compound is desired, so prepare this compound by asymmetric synthesis or adopt chirality adjuvant to prepare this compound by deriving, wherein, obtained non-enantiomer mixture is separated and cracking adjuvant group to provide the enantiomer of pure expectation.Alternatively, basic functionality is comprised (such as at molecule, amino) or acidic functionality (such as carboxyl) when, diastereomeric salt is formed by the acid of suitable optical activity or alkali, subsequently diastereomer is split, form enantiomer by fractional crystallization well known in the art or chromatography thus, reclaim pure enantiomer subsequently.
Phrase used herein " blocking group " refers to protects potential reactive functional groups by the temporary substituent of the impact of less desirable chemical conversion.The example of these blocking groups comprises respectively: the acetal of the ester of carboxylic acid, the silyl ether of alcohol, aldehyde and ketone and ketal.This area has summary (Greene, the T.W. of blocking group chemistry; Wuts, P.G.M.Protective Groups in Organic Synthesis, the third edition; Wiley:New York, 1999).
Except as otherwise noted, " stereoisomer " refers to a stereoisomer of the compound of another stereoisomer being substantially free of compound.Therefore, there is the contrary enantiomer that the pure compound of the stereoisomerism of a chiral centre can be substantially free of compound.Having the pure compound of the stereoisomerism of two chiral centres can substantially containing other diastereomer of compound.The pure compound of typical stereoisomerism comprises other stereoisomers higher than a stereoisomer of the compound of about 80% weight and the compound lower than about 20% weight, such as, a stereoisomer of compound is higher than about 90% weight, and another stereoisomer of compound is lower than about 10% weight, or compound stereoisomer higher than about 95% weight and another stereoisomer of compound lower than about 5% weight, or compound stereoisomer higher than 97% weight and another stereoisomer of compound lower than about 3% weight.
If there are differences between described structure and the given title of this structure, be so as the criterion with described structure.In addition, the spatial chemistry as the spatial chemistry of fruit structure or a part for structure does not show with the form of such as solid line or dotted line, and a part for so described structure or institute's structure is interpreted as comprising its all stereoisomer.
As mentioned above, the present invention relates to the compound according to general formula I:
For the compound of general formula I, variables A is (CHR
1)
mor C (O) and W is selected from following groups: – C (O) – (CH
2)
p-;-C (O) [-CH
2-CH
2-O]
n-,-[CH
2-CH
2-O]
n-(CH
2)
2-， – C (O)-[CH (R
3)
t]
q-,-(CH
2)
m-O-(CH
2)
n-,-(CH
2)
m-S-(CH
2)
n-,-(CH
2)
m-S (O)-(CH
2)
n-,-(CH
2)
m-S (O)
2-(CH
2)
n-, and-(CH
2)
m-NR
a-(CH
2)
n-.
Variable Y in general formula I is selected from: – NH-,-NR
2-, or
and X is selected from: – (C
1-C
10) alkylidene-(C
3-C
10) arlydene ,-(C
3-C
10) arlydene ,-(C
3-C
10) Ya Fangji – (C
1-C
10) alkylidene--, phenylene ， – (C
1-C
10) alkylidene-(C
3-C
10) ring alkylidene ,-(C
3-C
10) ring alkylidene, or-(C
3-C
10) ring Ya Wan Ji – (C
1-C
10) alkylidene-.For the compound of some general formula Is, X is-(C
3-C
10) arlydene, such as, phenylene group.
Substituent R in general formula I
1and R
2separately be selected from: H ,-(C
1-C
10) alkyl ， – C (O)-(C
1-C
10) alkyl, benzyl ,-(C
3-C
10) cycloalkyl, or-(C
3-C
10) aryl, and radicals R
aand R
bseparately be selected from following groups: H ,-OH ,-(C
1-C
10) alkyl ,-[CH
2-CH
2-O]
n-(CH
2)
2-T ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-Z, benzyl ,-(C
3-C
10) cycloalkyl ,-(C
3-C
10) aryl-(C
1-C
10) alkylidene ,-(C
3-C
10) aryl, halo-(C
1-C
10) alkyl, hydroxyl-(C
1-C
10) alkyl ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-.For the compound of some general formula Is, R
aand R
band nitrogen bonded thereto together forms (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl, (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl can comprise further and is selected from N, one or more than one hetero atom of S or O.
Z in general formula I can be selected from: – OH ,-O (C
1-C
10) alkyl,
substituent R
cbe selected from :-OH ,-O (C
1-C
10) alkyl ,-O benzyl ,-O (C
3-C
10) cycloalkyl ,-O (C
3-C
10) aryl ,-O-(C
1-C
10) alkylidene-(C
3-C
10) aryl, or-O-(C
1-C
10) alkylidene--(C
3-C
10) cycloalkyl, and R
3be selected from: H, halogen ,-OH ,-NH
2， – (CH
2)
p-COOH ， Huo – (CH
2)
p-NH
2.
In general formula I, T is selected from: – H ， – OH ,-COOH ， Huo – NR
dr
eand as T Shi – NR
dr
etime, substituent R
dand R
eseparately be selected from: H, chemical bond ,-OH ,-(C
1-C
10) alkyl, or-(C
3-C
10) heteroaryl-(C
1-C
10) alkylidene.
Subscript m, n, p, q, t and r are separately 0,1,2,3,4,5,6,7,8,9 or 10; And chelator group D is:
For the compound of general formula I, any alkyl, alkylidene, aryl, arlydene, heteroaryl, heteroarylidene, cycloalkyl, ring alkylidene, Heterocyclylalkyl or heterocycloalkylene group are optionally replaced by 1,2 or 3 substituent groups being selected from following groups :-(C
1-C
10) alkyl ,-(C
1-C
10) haloalkyl ,-(C
1-C
10) aminoalkyl ,-(C
1-C
10) alkylidene-COOH ,-(C
1-C
10) hydroxy alkyl ,-OH, halogen ,-NH
2,-COOH ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-X ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-， is with – NR
dr
e.
In one of the compound of general formula I of the present invention, X is phenylene, and subscript r is 1 and D is
metal-chelator DOTA.According to these conditions, the compound of general formula I I is as follows.For the compound of some general formula Is I, A is (CHR
1)
m, W is C (O)-(CH
2)
7-or-C (O)-(CH
2)
10-group, and Y is
In one embodiment, A is (CHR
1)
m, wherein R
1be hydrogen, m is 2.For the compound of some general formula Is I, R
aand R
band nitrogen bonded thereto together forms (C
3-C
6)-Heterocyclylalkyl, it is selected from: piperidines, piperazine, morpholine, thiomorpholine, isothiazolidine, isoxazole alkane, pyrrolidine, imidazolidine, Thiazolidine or oxazolidine.For the compound of some general formula Is I, R
abe-H and R
bbe
wherein, R
dand R
ebe separately :-(C
3-C
10) heteroaryl-(C
1-C
10) alkylidene, such as, R
dand R
ebe separately:
The compound meeting exemplary general formula I I defined above is as follows:
The compound of other exemplary general formula Is or general formula I I includes but not limited to the compound listed by following table 1.Although some exemplary compounds adopt spatial chemistry to describe, should be understood that, the present invention includes all possible stereoisomer of compound, such as, diastereomer.
Table 1
The pharmaceutically acceptable salt of the compound of illustrational general formula I of the present invention and general formula I I and/or solvate are also within the scope of the invention above.In some embodiments, chelator group, such as DOTA group, not with radionuclide generation complexation.When DOTA is non-complexation, the hydroxy-acid group of DOTA group can be the form of free acid or the form of salt.Free hydroxy-acid group can be esterified with the prodrug forms of the compound obtaining general formula I or general formula I I.Suitable ester prodrugs comprises various different Arrcostab, comprises, saturated with undersaturated C
8to C
18fatty acid.
Compound of the present invention is glutamic acid-carbamide-lysine (GUL-) or glutamic acid-carbamide-glutamic acid (GUG) analog, and wherein, chelator group is by connector and the coupling of GUL-or GUG-group.
As discussed further below, the length of connector group and chemical property are considered to the binding affinity that can affect compound of the present invention and destination organization.Therefore, the radionuclide complex in connector with the piperazine-triazine-general formula I of p-aminophenyl methyl D OTA group or the compound of general formula I I is observed and is gathered in tumor tissues relative to nonneoplastic tissue (such as, blood, heart, lung, liver, spleen, stomach, large intestine and small intestinal, testis, skeletal muscle, bone, brain and fatty tissue) with higher degree.
In addition, these compounds are removed fast by kidney.Observe within the time period of 96 hours, the compound containing piperazine-triazine radical-p-aminophenyl methyl D OTA be originally gathered in kidney is removed fast by kidney after longer interval.Such as, the compound of general formula I or general formula I I is gathered in kidney relative to tumor with higher degree in 4 hours upon administration.But the concentration of compound of the present invention does not change in time in tumor.Therefore, the tumor levels of the compound of general formula I or the general formula I I tumor levels of 4 hours and their 24 hours and 96 hours upon administration is upon administration similar.
Compound based on general formula I or general formula I I is used as radio-contrast agent or radiopharmaceutical, by different radionuclides and compound complexation.The example of suitable radionuclide is selected from: the radionuclide of actinium series, group of the lanthanides and transition metal, such as,
111in,
90y,
68ga,
64cu
153gd,
155gd,
157gd,
59fe,
225ac,
212bi,
213bi,
55co,
67cu,
165dy,
166ho,
192ir,
223ra,
186re,
188re,
105rh,
212pb,
213pb,
149tb,
227th,
153sm,
89sr,
117msn,
169yb,
90y,
86y,
89zr and
177lu.
With exemplary radionuclide
177the example of the general formula I of Lu complexation or the compound of general formula I I is illustrational those or its pharmaceutically acceptable salt or solvate in following table 2.
Table 2
Fig. 1 and Fig. 2 illustrates GUL-[piperazine-triazine radical-p-aminophenyl methyl]-DOTA-according to general formula I or general formula I I in LNCap xenograft mouse body
177the biodistribution research result of Lu complex, and Fig. 3 illustrates GUL-[alkylidene thiourea]-DOTA-in LNCap xenograft mouse body
177the biodistribution research result of Lu complex.
As illustrational by block diagram in these figures, complex (A), (B) and (C) are to be gathered in kidney and tumor than degree higher in its hetero-organization.In fact, 4 hours upon administration, the concentration that viewed complex (A), (B) and (C) are respective in kidney was higher than the concentration in tumor.But, as illustrational in Fig. 1 to Fig. 3 institute, after administration 24 hours and 96 hours, GUL-of the present invention [piperazine-triazine radical-p-aminophenyl methyl]-DOTA-in LNCap tumor cell
177the concentration of Lu complex (A) and (B) remains unchanged, and reduces in the interval that these are longer by the concentration of the complex compared (C) in LNCAP tumor cell.
These results are beyond thought and illustrate that the radionuclide complex of the compound of general formula I or general formula I I has stronger ability to be gathered in tumor cell.And as Fig. 1 and Fig. 2 is illustrational, complex of the present invention (A) and (B) remove fast from kidney.Because the radionuclide complex of the compound of general formula I or general formula I I is gathered in tumor and is removed fast by kidney, so the radionuclide complex of the compound of general formula I or general formula I I is the candidate therapeutic agent being used for the treatment of cancer (such as carcinoma of prostate).
LNCaP tumor is gathered in complex of the present invention but the further confirmation of removing from its hetero-organization comprising kidney more rapidly after delivering medicine to the mice with LNCap tumor use GUL-[piperazine-triazine radical-p-aminophenyl methyl]-DOTA-
177obtain in the biodistribution research of the independent prolongation of Lu complex (D), illustrate as follows.
As illustrational in the block diagram in Fig. 4, to be gathered in kidney and tumor than degree higher in its hetero-organization in complex of the present invention shorter interval upon administration.Such as, the concentration of complex (D) in kidney and tumor along with administration after time variations in first eight hours section and increasing gradually.Such as, but in longer interval, little within the time period of 96 hours 24, the concentration of complex (D) in kidney reduces, and observable change does not occur the concentration of complex (D) in tumor.
In order to study the pharmacokinetics of tumor retention and kidney removing further, biodistribution research is extended to three weeks.After administration complex (D), the fabric analysis of 1 week shows that observable change does not occur the IC of this complex in LNCaP tumor cell.After administration complex (D) in the kidney of 1 week concentration significantly lower than concentration in the kidney of the complex (D) of interval (such as, after administration in eight hours) comparatively early.
3 weeks upon administration, the intratumoral concentrations of fabric analysis display complex (D) reduced.But relative to the reduction of concentration in the kidney of complex (D), the reduction of the intratumoral concentrations of this complex is less.As mentioned above, the biodistribution research of prolongation confirms observed result originally, and within the identical time period, the reduction in kidney of the concentration of complex (D) is than faster in tumor.In sum, these results illustrate that the radionuclide complex of the present invention of general formula I or general formula I I has higher affinity relative to nonneoplastic tissue (such as, blood, heart, lung, liver, spleen, stomach, large intestine and small intestinal, testis, skeletal muscle, bone, brain and fatty tissue) to tumor cell.Therefore, the compound of general formula I and general formula I I is candidate therapeutic agent for selective imaging LNCap tumor cell or developing agent.
Relative to the inhibitor ((7S of known PSMA, 14S, 18S)-7-amino-1-(1-(carboxymethyl)-1H-imidazoles-2-base)-2-((1-(carboxymethyl)-1H-imidazoles-2-base) methyl)-8,16-dioxy-2,9,15,17-tetra-azepine four azepine icosane-14,18,20-tricarboxylic acids (
99mtc-MIP-1405)), in the Human Prostate Cancer Cells competitive binding assay using the PSMA positive (+) LnCap cell, the compound of mutual-through type I or general formula I I screens, and calculates IC
50value.
In brief, LNCaP Human Prostate Cancer Cells is available from American type culture collection (Rockville, MD).LNCaP cell is remained in the RPMI-1640 culture medium being supplemented with 10% hyclone (FBS).Radiolabeled compound and cold derivant competition binding LNCaP is performed according to disclosed method.Cell is with about 4x10
5cells/well to be seeded in 12 hole flat boards and to hatch 48 hours in moistening couveuse under 37 DEG C/5% carbon dioxide conditions, adds compound subsequently.Prepare the compound solution of general formula I or general formula I I and dilute in not containing the cell culture medium of serum, the described cell culture medium not containing serum comprises 0.5% bovine serum albumin (BSA) and 3nM
99mtc-MIP-1405 (known inhibitor).Total binding is by hatching not containing test compounds
99mtc-MIP-1405 measures.Flat board at room temperature hatches 1 hour.From flat board, take out cell and be transferred in eppendorff pipe.Sample micro-centrifugal 15 seconds with 10K x g.Siphon away culture medium and wash granule twice by being scattered in fresh analysis culture medium, carrying out micro-centrifugal subsequently.
99mthe Cell binding of Tc-MIP-1405 by carrying out counting to determine to cell pellet in automatic gamma counter.Table 3 illustrates the on-radiation of representational general formula I I
175the IC of Lu complex
50value.
Table 3
As institute is illustrational above, the compound of general formula I of the present invention and general formula I I is combined with the PSMA of the surface expression at prostate gland cancer cell and has the IC in nanomolar range
50value.Therefore, compound of the present invention is the candidate's radiation treatment agent for suppressing carcinoma of prostate tumor growth.It should be noted that above and in some structures described in content disclosed by the invention, may have or may not have the interactional dotted line or solid line that represent and infer between some functional group and metallic radionuclide.These descriptions only illustrate possible binding interactions, but it is not intended the metal-ligand interaction that these descriptions are interpreted as the uniquely possible or reality be present in described special metal complex.Such as, one or more than one possibility in macro ring azepine group, perhaps, the total bonding even probably contributed between metal ion and cheland interacts.
Fig. 5 illustrates that exemplary lutetium complex of the present invention suppresses the interior curative effect of the LNCaP tumor growth in Mice Body.The suppression of tumor growth is by (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(dimethylamino)-the 6-((4-((1 by 450 μ Ci, 4,7,10-tetra-(carboxymethyl)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) each mice that the lutetium complex of 1,3-propanedicarboxylic acid delivers medicine in seminar measures.Mice administration saline in matched group.Gross tumor volume in mice test group and matched group measures twice weekly.Receive and significantly reduce relative to the gross tumor volume of matched group small mouse according to the gross tumor volume of the mice of lutetium complex of the present invention.
In fact, as Fig. 5 is illustrational, after administration complex of the present invention, the LNCaP gross tumor volume of the mice in test group is observed the value of the gross tumor volume be reduced to when starting lower than research.On the contrary, in the mice accepting saline, the volume of LNCaP tumor increases.These observed results illustrate that the radionuclide complex of the compound of general formula I of the present invention and general formula I I is effective in the growth suppressing carcinoma of prostate in body.
According to another embodiment of the present invention, the radiometal complexes of the compound of general formula I and general formula I I is for making carcinoma of prostate imaging and for the neoplasm metastasis in subject.In brief,
68ga and (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid complexation and the complex obtained is delivered medicine to the patient suffering from carcinoma of prostate.Subsequently, of the present invention in administration
68after Ga complex 1 hour and 3 hours, use such as
68ga-PSMA PET/CT scanner carries out imaging to described patient.As Fig. 6 is illustrational, except PSMA specific lesions being detected in prostata tissue self, in lymph node and bone, PSMA specific lesions also detected.Some developing agents also can video picture in the bladder of patient in 1 hour, and it is eliminated by scanning in three hours.Radionuclide imaging image in Fig. 6 further illustrates complex of the present invention and accumulates in lachrymal gland and salivary gland, kidney, liver and urinary system bladder.In general, this imaging research supports the suitable radio-contrast agent of radiometal complexes as cancer (such as, carcinoma of prostate) of compound of the present invention.
Because compound and the radionuclide complex thereof of general formula I and general formula I I can have one or more than one chiral centre, so, the present invention includes enantiomer and all diastereomers.And the L-type of natural amino acid and D type all can be used for the compound synthesizing general formula I and general formula I I.That is, the present invention includes the stereoisomer of the compound of general formula I and general formula I I and radionuclide complex thereof, tautomer and prodrug.
As mentioned above, the radionuclide complex of the compound of general formula I or general formula I I can comprise one or more than one radionuclide, described radionuclide is suitable for use as radio-contrast agent or is used as to treat with the not controlled of cell and the therapeutic agent of the disease that fast breeding is relevant, described cell such as, expresses the prostate gland cancer cell of PSMA.Therefore, in one embodiment, pharmaceutical composition provided by the invention comprises complex, and described complex comprises the compound of metal and general formula I or general formula I I, its salt, solvate, stereoisomer or tautomer and pharmaceutically acceptable carrier.
In general, the metal complex of the compound of general formula I or general formula I I or its pharmaceutically acceptable composition palatable take administration or by parenteral route, usually pass through drug administration by injection.Parenteral route includes but not limited to: intravenous injection and infusion, intramuscular injection and infusion, intra-arterial injection and infusion, intrathecal injection and infusion, intracapsular injection and infusion, injection and infusion in frame, intracardiac injection and infusion, intradermal and infusion, peritoneal injection and infusion, transtracheal injection and infusion, subcutaneous injection and infusion, epidermis hemostasis and infusion, intra-articular injection and infusion, capsule hemostasis and infusion, arachnoidea hemostasis and infusion, intraspinal injection and infusion and breastbone inner injection and infusion.In some embodiments, compound or its drug composition oral administration.These compositionss can adopt tablet, pill, capsule, semisolid, powder, solution, suspension, elixir, aerocolloidal form or any other suitable compositions.
According on the other hand, the invention provides the pharmaceutical composition being suitable for in-vivo imaging and radiation treatment.Suitable pharmaceutical composition can comprise the radio-contrast agent of the amount being enough to imaging or have the radiometal chelation complex of the radiation treatment agent of radionuclide or the compound of general formula I or general formula I I and pharmaceutically acceptable radioactivity supporting agent, wherein, described radionuclide is element, that is, radioactive iodine.Radioactivity supporting agent should be suitable for injection or suck, such as, and human serum albumin; Aqueous buffer solution, such as, three (methylol) aminomethane (or its salt), phosphate, citrate, bicarbonate, etc.; Sterilized water; Normal saline; And the solion of balance, this solution comprises chloride and/or bicarbonate or normal plasma cation (such as, calcium, potassium, sodium and magnesium).
Developing agent in radioactivity supporting agent or the concentration of therapeutic agent should be enough to provide gratifying imaging.Such as, when using aqueous solution, dosage is about 1.0 millicurie to 50 millicuries.But, deliver medicine to patient and determined by the clinicist carrying out treating for the actual dose of imaging or therapeutic purposes.Developing agent or therapeutic agent should to be used to maintain in patient body about 1 little of 24 hours, although the longer or shorter time period is acceptable.Therefore, can prepare and comprise the easily ampulla of 1mL aqueous solution to 10mL aqueous solution.
Development can be implemented in a usual manner, such as, by injecting enough developer compositions to provide fully development and to adopt the suitable machine of such as gammacamera and so on to carry out scanning implementing subsequently.In some embodiments, the region in patient body is made to carry out the method for developing, such as, make the method for one or more than one tissue development of expression prostate specific membrane antigen (PSMA) comprise the steps: (i) by diagnosis effective dose with the general formula I of radionuclide complexation, the compound administration of general formula I I or general formula III in patient to make one or more than one tissue and general formula I of expression PSMA, the radionuclide complex thereof of the compound of general formula I I or general formula III; And (ii) records the Radionuclide imaging image of one or more than one tissue.In some embodiments, the tissue be developed is prostata tissue or prostate cancer tissue.According to method of the present invention, develop by by diagnosis effective dose with the compound of the general formula I of radionuclide complexation, deliver medicine to patient to implement with the compound of the general formula I I of radionuclide complexation or with the compound of the general formula III of radionuclide complexation or the pharmaceutically acceptable salt of complex of the present invention or solvate.
Therefore, in one embodiment, imaging is implemented by the radionuclide complex of the compound using general formula III.
In general formula III, G is
l is selected from: – NH-(C
1-C
10) alkylidene-， – NH-(C
1-C
10) alkylidene-C (O)-， – C (O)-(C
1-C
10) alkylidene-， – C (O)-(C
1-C
10) alkylidene-C (O)-or-C (O)-(C
1-C
10) alkylidene
and variable R
aand R
bseparately be selected from: H ,-OH ,-(C
1-C
10) alkyl ,-[CH
2-CH
2-O]
n-(CH
2)
2-T ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-Z, benzyl ,-(C
3-C
10) cycloalkyl ,-(C
3-C
10) aryl-(C
1-C
10) alkylidene ,-(C
3-C
10) aryl, halo-(C
1-C
10) alkyl, hydroxyl-(C
1-C
10) alkyl ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-, or R
aand R
band nitrogen bonded thereto together forms (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl, (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl can comprise further and is selected from N, one or more than one hetero atom of S or O.
Z in general formula III is selected from: – OH ,-O (C
1-C
10) alkyl,
and R
dand R
eindependently selected from following groups: H, chemical bond ,-OH ,-(C
1-C
10) alkyl, or-(C
3-C
10) heteroaryl-(C
1-C
10) alkylidene.Subscript " n " be selected from 0,1,2,3,4,5,6,7,8,9 or 10 integer.For the compound of general formula III, any alkyl, alkylidene, aryl, arlydene, heteroaryl, heteroarylidene, cycloalkyl, ring alkylidene, Heterocyclylalkyl or heterocycloalkylene group are selected from 1,2 of following groups or 3 substituent groups optionally replace :-(C
1-C
10) alkyl ,-(C
1-C
10) haloalkyl ,-(C
1-C
10) aminoalkyl ,-(C
1-C
10) alkylidene-COOH ,-(C
1-C
10) hydroxy alkyl ,-NH
2,-COOH ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-X ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-， is with – NR
dr
e.
Metal for the formation of complex is radionuclide, and it is selected from:
111in,
90y,
68ga,
64cu
153gd,
155gd,
157gd,
59fe,
225ac,
212bi,
213bi,
55co,
67cu,
165dy,
166ho,
192ir,
223ra,
186re,
188re,
105rh,
212pb,
213pb,
149tb,
227th,
153sm,
89sr,
117msn,
169yb,
90y,
86y,
89zr and
177lu.
Deliver medicine to the amount of the compound of the general formula I of patient, general formula I I or general formula III or comprise radioactive metal and depend on the normally used multiple physiologic factor of clinicist according to the amount of the preparation of the compound or its salt of general formula I or general formula I I, solvate, stereoisomer or tautomer, comprise the characteristic of development to be performed, for body weight and the medical history of the patient of the tissue treating targeting that develops and pending development.
And, the invention describes and be a kind ofly used for the treatment of diagnosis and suffer from the method for the patient of cancer, described method is by delivering medicine to this patient to implement in conjunction with complex by the prostate specific membrane antigen (PSMA) comprising triazine connector for the treatment of effective dose.In a kind of embodiment of this method, the Prostato-specific membrane antigen (PSMA) comprising triazine connector in conjunction with complex is and the compound of the general formula I of radionuclide complexation, general formula I I or general formula III or the pharmaceutically acceptable salt of described complex or solvate.The radionuclide complex of the compound of above-mentioned general formula I, general formula I I and general formula III is relative to not expressing tissue (such as, kidney, liver, spleen, heart, blood, lung, muscle, bone, large intestine, small intestinal, brain or the fat) preferential retention of PSMA in the tumor tissues of expressing PSMA.Except carcinoma of prostate, the radionuclide complex of the compound of general formula I or general formula I I can also be the candidate therapeutic agent being used for the treatment of breast carcinoma, colon cancer, the brain cancer, pulmonary carcinoma, hepatocarcinoma or renal carcinoma.
Therefore, can the present invention of easy to understand general description with reference to embodiment hereafter, embodiment hereafter provides in the illustrated manner, is not intended to limit the present invention.
embodiment
Cell culture general purpose discipline
Human prostata cancer LNCaP cell is available from American type culture collection.Except as otherwise noted, cell culture supply comes from Invitrogen.LNCaP cell maintains 37 DEG C/5%CO
2being supplemented with in the RPMI-1640 culture medium of 10% hyclone (Hyclone), 4mM L-glutaminate, 1mM sodium propionate, 10mM hydroxyethyl piperazine ethanesulfonic acid (hepes), 2.5mg/mL D-Glucose, 50 μ g/mL gentamycins in the moistening couveuse under condition.From flask, take out cell be used for going down to posterity, transfer them to 12 holes analysis flat boards to mouse inoculation or by employing 0.25% trypsin/DETA incubated cell.
Competition binding general purpose discipline
Detect containing PSMA inhibitor on-radiation lutecium with
99mtc-((7S, 14S, 18S)-7-amino-1-(1-(carboxymethyl)-1H-imidazoles-2-base)-2-((1-(carboxymethyl)-1H-imidazoles-2-base) methyl)-8,16-dioxy-2,9,15,17-tetra-azepine eicosane-14,18,20-tricarboxylic acids) ability of PSMA in competition binding LNCaP cell.LNCaP cell (triplicate, 4x 10 in 12 hole flat boards
5cells/well) and 3nM
99mthere is 1-10 in Tc-complex, hatches 1 hour under the condition of 000nM test compounds in the RPMI culture medium containing 0.5%BSA.Drawing with pipettor lightly moves in Eppendorf pipe by cell, washes twice and count with RPMI+0.5%BSA.
Mice study
All zooscopies are ratified by animal care and use committee for the humanity nursing of laboratory animal and the guide of use according to U.S. Public Heath Service policy.At the standard conditions, mice is housed in the facility of approval, with light/dark circulations in 12 hours and freely subsisting and water.Male athymic NCr-nu/nu mice is purchased from Taconic.For for mice Inoculation, LNCaP cell is with 10
7cell/ml is resuspended in cell culture medium: in the 1:1 mixture of Matrigel (BD Biosciences).At the right side of each mice injection 0.25ml cell suspending liquid.When tumor reaches about 100-400mm
3time, mice is used for tissue distribution research.
Tissue distribution
177the quantitative analysis of the tissue distribution of the compound of Lu-labelling is carried out in each group of the male NCr-nu/nu mice with LNCaP cell xenografts.By tail vein using the constant volume compound of 0.05mL as bolus infusion (about 10 μ Ci/ mices) administration.Time point shown after injection adopts carbon dioxide to implement euthanasia by suffocating to animal (n=5/ time point).Segmentation, resection organization are (such as, blood, heart, lung, liver, spleen, kidney, stomach, large intestine and small intestinal (with inclusions), testis, skeletal muscle, skeleton, brain, fat) and tumor, weigh net weight and count in automatic γ-calculating instrument.The time m-radioactive level of tissue is expressed as the injected dose percentage ratio (%ID/g) of every gram of tissue.
Interior curative effect
Be about 100mm with average external volume
3to 500mm
3the mice of LNCaP xenograft be appointed as matched group or treatment group (n=10 mice/group) at random.Mice administration saline in matched group, and the mice in test group accepts the general formula I of the present invention of 450 μ Ci/ mices or the compound of general formula I I
177lu-complex.Each animals iv administration volume is the test substances of 0.05mL.Tumor size adopts digital calipers measure twice weekly and use formula (4/3x Π x width
2x length)/6 calculating gross tumor volumes.Carry out measuring until gross tumor volume in supporting agent group reaches maximum (1, the 500mm that IACUC guide allows
3).
Universal synthesis method
To the general step of the compound of synthesis general formula I with for the general step of the compound of general formula I and radionuclide complexation is described.Although hereafter illustrate the code for the compound complexation by lutecium and general formula I, should be understood that, similar synthesis step can be followed for other radionuclides of complexation.Therefore, although specifically show lutecium, with other radionuclides (such as In, Y, Zr, Ga in each different embodiment hereinafter described, Lu, Cu, Gd, Ac Fe, Bi Co, Dy Ho, Ir, Ra, Re, Rh, Sr or Sm) complex also within the scope of the invention.In addition, should be understood that, the various different isotope of these elements also can by complexation, such as,
111in,
90y,
68ga,
64cu
153gd,
155gd,
157gd,
59fe,
225ac,
212bi,
213bi,
55co,
67cu,
165dy,
166ho,
192ir,
223ra,
186re,
188re,
105rh,
212pb,
213pb,
149tb,
227th,
153sm,
89sr,
117msn,
169yb,
90y,
86y,
89zr and
177lu.
For the formation of the General experimental condition of lutetium complex
By the lutetium complex of the compound of general formula I from relating to commercially LuCl
3separate easily in the reaction contacted with according to the compound of general formula I.In brief, in sealed vial, make 10 of the general formula I of the expectation in the equal-volume mixture of 1:1 acetonitrile and phosphate buffer or the compound of general formula I I
-6m to 10
-4the solution of M and LuCl
3contact.Reactant mixture is heated to 100 DEG C, continues 30 minutes to 45 minutes.After cooling, by completing and purity of reverse-phase HPLC (RP-HPLC) analytical reactions, and if if required, RP-HPLC or C18 Sep Pak post is used to carry out purification.After purification, the grand mean productive rate of the product of lutecium complexation is about 20% to about 99%.But after HPLC purification, radio-chemical purity is constant is >=95%.
Initial results shows be low to moderate 10
-6under the concentration conditions of M, the compound of mutual-through type I or general formula I I carries out radioactive label, and under this concentration conditions of reagent, radio chemistry productive rate (RCY) is approximately≤and 80%.In order to reach higher RCY, higher than 95%, improving reaction temperature and the reagent concentration in reactant mixture is increased to 10
-4m.
Similar synthesis strategy is for merging other radionuclides.And the introducing of radionuclide can be carried out before the deprotection of the compound of general formula I or general formula I I or after the deprotection of the compound of general formula I.
The synthesis of the compound of the exemplary general formula I based on triazine-piperazine, general formula I I or general formula III
Option A, option b and scheme C illustrate the general synthesis code of the compound for exemplary general formula I.In brief, p-aminophenyl methyl DOTA is contacted with cyanuric chloride, make the product that obtains and amine react subsequently.The product formed thus subsequently with GUG-or GUL-connector-piperazine group contacts, thus obtain the compound of general formula I.
Option A.
Option b
Scheme C
Embodiment 1:(2S)-2-(3-((1S)-1-carboxyl-5-(8-((4-(dimethylamino)-6-((4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1; 3,5-triazine-2-base) amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1:(18S, 22S)-tri-tert 1-(9H-fluorenes-9-base)-3,12,20-tri-oxygen-2-oxa--4,13,19,21-tetra-azepine lignocerane-18,22,24-tricarboxylic ester.
At room temperature stir (S)-di-t-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate (1.9677g, 4.03mmol), 8-((((9H-fluorenes-9-base) methoxyl group) carbonyl) is amino) sad (1.84g, 4.84mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) (EDCI; (0.770g, 4.03mmol), HOBt (0.544g, 4.03mmol) and DIPEA (DIPEA; (2.0mL) DCE (100mL) solutions overnight).Evaporating solvent, obtains residue, and this residue is by silica gel column chromatography (Biotage), use the mixture of DCM/MeOH to carry out purification as eluant, thus obtain white solid (18S, 22S)-tri-tert 1-(9H-fluorenes-9-base)-3,12,20-tri-oxygen-2-oxa--4,13,19,21-tetra-azepine lignocerane-18,22,24-tricarboxylic ester (2.099g, 61%).MS(ESI),851.2(M+H)
+。
Step 2. (S)-di-t-butyl 2-(3-((S)-6-(the amino caprylyl of 8-)-1-(tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate.
To (18S, 22S)-tri-tert 1-(9H-fluorenes-9-base)-3,12,20-tri-oxygen-2-oxa--4,13,19,21-tetra-azepine lignocerane-18, piperidines (4.0mL) is added in DMF (4.0mL) solution of 22,24-tricarboxylic ester (1.983mg, 2.333mmol).At room temperature stir the mixture 3 hours, subsequently, evaporation under reduced pressure solvent, thus obtain residue, this residue is by column chromatography, and adopt Biotage SP4 post and gradient elution to carry out purification, this gradient elution uses 100%DCM to DCM: the 1:1 of methanol is as eluting solvent.Product (S)-di-t-butyl-2-(3-((S)-6-(the amino caprylyl of 8-)-1-(the tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate (1.039mg, 71%) obtained thus uses
1h NMR and mass spectrum characterize.
1H NMR(400MHz,DMSO-d
6)7.71(t,J＝5.2Hz,1H),6.29(d,J＝8.0Hz,1H),6.25(d,J＝8.4Hz,1H),5.74(brs,2H),4.05-3.91(m,2H),3.01-2.88(m,2H),2.63(t,J＝6.8Hz,2H),2.20-1.22(m,49H)；MS(ESI),629.3(M+H)
+。
Step 3. (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(dimethylamino)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid.
DIPEA (0.10mL) is added in DCM (4.0mL) solution of p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (67.8mg, 0.080mmol) and cyanuric chloride (14.7mg, 0.080mmol).At room temperature stir this solution 3 hours, subsequently under nitrogen flowing except desolventizing, obtain residue.(S)-di-t-butyl 2-(3-((S)-6-(the amino caprylyl of 8-)-1-(tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate (50.3mg, 0.08mmol) and K is added in DMSO (4.0mL) solution of residue
2cO
3(100mg).At room temperature stirred suspension continues about 2 hours, subsequently to the tetrahydrofuran solution adding dimethylamine (in 0.3mL, THF 2.0M) in reactant mixture.At room temperature after continuous stirring 16 hours, lyophilizing reactant mixture, obtains thick triazine intermediate.By adding TFA (4.0mL) and DCM (1.0mL) and at room temperature stirred reaction mixture carries out deprotection to crude product in 4 hours.Use nitrogen current to remove desolventizing and obtain residue; this residue uses Biotage SP4; purification is carried out by C18 cylinder; obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(dimethylamino)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1,3,5-triazines-2-base amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid (67mg).
1H NMR(400MHz,DMSO-d
6)7.83-7.60(m,3H),7.17(d,J＝8.0Hz,2H),6.32(d,J＝8.0Hz,1H),6.28(d,J＝8.4Hz,1H),4.10-1.27(m,61H)；MS(ESI),1091.4(M+H)
+。
Step 4. (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(dimethylamino)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(dimethylamino)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3; 5-triazine-2-base is amino) caprylyl) amyl group) urea groups) add LuCl in 1,3-propanedicarboxylic acid (5.7mg, 0.00522mmol)
3(1.46mL, 0.00357mmol/mL, 0.00522mmol) and acetonitrile (0.50mL).At 95 DEG C, reacting by heating mixture continues 1 hour; lyophilizing subsequently; obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(dimethylamino)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex (6.2mg).MS(ESI),1263.0(M+H)
+。
Embodiment 2. (S)-2-(3-((S)-1-carboxyl-5-(8-((4-(piperidin-1-yl)-6-((4-(((S)-1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1; 3,5-triazine-2-base) amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (2S)-2-(3-((S)-1-carboxyl-5-(8-(4-(piperidin-1-yl)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) and in DCM (2.0mL) solution of cyanuric chloride (9.2mg, 0.050mmol) add DIPEA (0.10mL).At room temperature stir this reactant mixture 2 hours, use nitrogen current except desolventizing subsequently, obtain residue.Obtained residue to be dissolved in DMSO (4.0mL) and to add (S)-di-t-butyl 2-(3-((S)-6-(the amino caprylyl of 8-)-1-(tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate (31.4mg, 0.05mmol) and K
2cO
3(100mg).At room temperature stirred suspension 2 hours, adds piperidines (0.10mL) subsequently.At room temperature stirred reaction mixture 14 hours again, lyophilizing subsequently, obtains triazine intermediate, carries out deprotection by adding the TFA (2.0mL) be dissolved in DCM (1.0mL) to this triazine intermediate.Deprotection passes through at room temperature stirred reaction mixture and carries out for 4 hours.After deprotection; use nitrogen current except desolventizing; obtain residue; this residue is by Biotage SP4; C18 cylinder is used to carry out purification; obtain white solid pure (2S)-2-(3-((S)-1-carboxyl-5-(8-(4-(piperidin-1-yl)-6-(4-((1; 4; 7,10-tetra-(carboxymethyl group)-Isosorbide-5-Nitrae; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1,3,5-triazines-2-base amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid (25.8mg).
1H NMR(400MHz,DMSO-d
6)7.75-7.60(m,3H),7.18(d,J＝7.2Hz,2H),6.33(d,J＝7.6Hz,1H),6.30(d,J＝8.0Hz,1H),4.12-1.24(m,65H)；MS(ESI),1131.2(M+H)
+。
Step 2. (2S)-2-(3-((S)-1-carboxyl-5-(8-(4-(piperidin-1-yl)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((S)-1-carboxyl-5-(8-(4-(piperidin-1-yl)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3; 5-triazine-2-base is amino) caprylyl) amyl group) urea groups) add LuCl in 1,3-propanedicarboxylic acid (9.2mg, 0.00814mmol)
3(1.60mL, 0.00513mmol/mL, 0.0082mmol) and acetonitrile (0.50mL).Reacting by heating mixture 1 hour at 95 DEG C; lyophilizing subsequently; obtain white solid (2S)-2-(3-((S)-1-carboxyl-5-(8-(4-(piperidin-1-yl)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex (9.4mg).MS(ESI),1302.2(M+H)
+。
Embodiment 3. (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-morpholinyl-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-morpholinyl-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) and in DCM (2.0mL) solution of cyanuric chloride (9.2mg, 0.050mmol) add DIPEA (0.10mL).Stirred at ambient temperature reacts 2 hours, uses nitrogen current except desolventizing subsequently, obtains residue.This residue to be dissolved in DMSO (4.0mL) and subsequently by (S)-di-t-butyl 2-(3-((S)-6-(the amino caprylyl of 8-)-1-(tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate (31.4mg, 0.05mmol) and K
2cO
3(100mg) add in DMSO solution.At room temperature stirred suspension continues 2 hours, adds morpholine (0.10mL) subsequently and at room temperature stirred reaction mixture 14 hours again.Lyophilizing reactant mixture, obtains triazine intermediate, adds TFA (2.0mL) and DCM (1.0mL) in this triazine intermediate.At room temperature stir this mixture 4 hours, thus produce deprotection effect, subsequently, use nitrogen current except desolventizing, obtain crude product residue.Biotage SP4 and C18 cylinder is used to carry out purification; obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-morpholinyl-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid (29.8mg).
1H NMR(400MHz,DMSO-d
6)7.75-7.65(m,3H),7.14(m,2H),6.55(m,2H),6.33(d,J＝8.0Hz,1H),6.30(d,J＝8.4Hz,1H),4.10-1.27(m,61H)；MS(ESI),1133.2(M+H)
+。
Step 2. (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-morpholinyl-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-morpholinyl-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-Isosorbide-5-Nitrae, 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) add LuCl in 1,3-propanedicarboxylic acid (10.4mg, 0.0092mmol)
3(1.80mL, 0.00513mmol/mL, 0.0092mmol) and acetonitrile (0.50mL).At 95 DEG C, reacting by heating mixture continues 1 hour; and lyophilizing subsequently; obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-morpholinyl-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex (9.9mg).MS(ESI),1304.9(M+H)
+。
Embodiment 4. (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(4-((4-carboxyl-1; 7; 10-tri-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-6-(piperazine-1-base)-1,3,5-triazines-2-base amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(4-((4-carboxyl-1; 7; 10-tri-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-6-(piperazine-1-base)-1,3,5-triazines-2-base amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) and in DCM (2.0mL) solution of cyanuric chloride (9.2mg, 0.050mmol) add DIPEA (0.10mL).At room temperature stirring reaction 2 hours.Use nitrogen current except desolventizing subsequently; obtain residue; this residue is dissolved in DMSO (4.0mL) also subsequently by (S)-di-t-butyl 2-(3-((S)-6-(the amino caprylyl of 8-)-1-(tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate (31.43mg, 0.05mmol) and K
2cO
3(100mg) add in DMSO solution.At room temperature stir the suspension lasts that obtains 2 hours, add piperazine (100mg) subsequently and at room temperature continue stirring 16 hours again.Lyophilizing crude reaction product subsequently, adds the triazine intermediate obtained thus, uses TFA (2.0mL) and DCM (1.0mL) to carry out deprotection.Deprotection is carried out by room temperature stirring to spend the night, use nitrogen current except desolventizing subsequently, obtain the residue of crude product, this crude product is by Biotage SP4, C18 cylinder is used to carry out purification, obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(4-((4-carboxyl-1, 7, 10-tri-(carboxymethyl group)-1, 4, 7, 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-6-(piperazine-1-base)-1, 3, 5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid (18.9mg).
1H NMR(400MHz,DMSO-d
6)8.85(m,2H),7.75-7.65(m,4H),7.16(m,2H),6.55(m,2H),6.32(d,J＝8.8Hz,1H),6.29(d,J＝8.4Hz,1H),4.11-1.23(m,61H)；MS(ESI),1132.2(M+H)
+。
Step 2. (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(4-((4-carboxyl-1; 7; 10-tri-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-6-(piperazine-1-base)-1,3,5-triazines-2-base amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(4-((4-carboxyl-1; 7; 10-tri-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-6-(piperazine-1-base)-1; 3; 5-triazine-2-base is amino) caprylyl) amyl group) urea groups) add LuCl in 1,3-propanedicarboxylic acid (7.8mg, 0.0069mmol)
3(1.80mL, 0.00385mmol/mL, 0.0069mmol) and acetonitrile (0.5mL).At 95 DEG C, reacting by heating mixture continues 1 hour; lyophilizing subsequently; obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(4-((4-carboxyl-1; 7; 10-tri-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-6-(piperazine-1-base)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex (8.3mg).MS(ESI),1303.6(M+H)
+。
Embodiment 5. (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(4-(3-carboxypropyl) piperidin-1-yl)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(4-(3-carboxypropyl) piperidin-1-yl)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid.
DIPEA (0.10mL) is added to p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) with cyanuric chloride (9.2mg, in DCM (2.0mL) solution 0.050mmol), and at room temperature stir the mixture lasting 2 hours.Subsequently, use nitrogen current except desolventizing, obtain residue, this residue is dissolved in DMSO (4.0mL).By (S)-di-t-butyl 2-(3-((S)-6-(the amino caprylyl of 8-)-1-(tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate (31.43mg, 0.05mmol) and K
2cO
3(100mg) add in DMSO solution, at room temperature stir the suspension lasts that obtains 2 hours, add 4-(piperidin-4-yl) butanoic acid (30mg) subsequently.After at room temperature stirring 16 hours, by reactant mixture lyophilizing, obtain triazine intermediate, this intermediate carries out deprotection by using TFA (2.0mL) and DCM (1.0mL) again.At room temperature stir after spending the night, use nitrogen current except desolventizing, obtain the crude product residue of title compound.Biotage SP4 and C18 cylinder is used to carry out purification; obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(4-(3-carboxypropyl) piperidin-1-yl)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid (18.8mg).MS(ESI),608.8(M/2+H)
+。
Step 2. (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(4-(3-carboxypropyl) piperidin-1-yl)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(4-(3-carboxypropyl) piperidin-1-yl)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3; 5-triazine-2-base is amino) caprylyl) amyl group) urea groups) add LuCl in 1,3-propanedicarboxylic acid (7.4mg, 0.006086mmol)
3(1.58mL, 0.00385mmol/mL, 0.006086mmol).Stirred reaction mixture 1 hour at 95 DEG C; lyophilizing subsequently; obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(8-(4-(4-(3-carboxypropyl) piperidin-1-yl)-6-(4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl amino)-1; 3,5-triazine-2-base is amino) caprylyl) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex (9.0mg).MS(ESI),1388.8(M+H)
+。
Embodiment 6. ((2S; 2'S)-2; 2'-(((((1S; 1'S)-((8; 8'-((6-((4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazines-2; 4-bis-base) two (urea two base)) two (caprylyl)) two (urea two base)) two (1-carboxyl pentane-5,1-bis-base)) two (urea two base)) two (carbonyl)) two (urea two base)) diglutaric acid lutetium complex.
Step 1. ((2S; 2'S)-2; 2'-(((((1S; 1'S)-((8; 8'-((6-((4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazines-2; 4-bis-base) two (urea two base)) two (caprylyl)) two (urea two base)) two (1-carboxyl pentane-5,1-bis-base)) two (urea two base)) two (carbonyl)) two (urea two base)) diglutaric acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) with cyanuric chloride (9.2mg, add DIPEA (0.10mL) in DCM (2.0mL) solution 0.050mmol), and at room temperature stir the mixture 2 hours.After stirring, use nitrogen current except desolventizing, obtain residue.This residue is dissolved in DMSO (4.0mL); and by (S)-di-t-butyl 2-(3-((S)-6-(the amino caprylyl of 8-)-1-(tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate (62.8mg, 0.10mmol) and K
2cO
3(100mg) add in the DMSO solution obtained.At room temperature stir the suspension lasts that obtains thus 72 hours, and lyophilizing subsequently, obtain triazine intermediate, this intermediate uses TFA (4.0mL) and DCM (1.0mL) to carry out deprotection.At room temperature stir TFA/DCM mixture overnight, use nitrogen current except desolventizing subsequently, obtain the crude product of solid title compound.By Biotage SP4, C18 cylinder is used to carry out purification to crude product, obtain pure white solid ((2S, 2'S)-2, 2'-(((((1S, 1'S)-((8, 8'-((6-((4-((1, 4, 7, 10-tetra-(carboxymethyl group)-1, 4, 7, 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1, 3, 5-triazine-2, 4-bis-base) two (urea two base)) two (caprylyl)) two (urea two base)) two (1-carboxyl pentane-5, 1-bis-base)) two (urea two base)) two (carbonyl)) two (urea two base)) diglutaric acid (10.0mg).MS(ESI),753.2(M/2+H)
+。
Step 2. ((2S; 2'S)-2; 2'-(((((1S; 1'S)-((8; 8'-((6-((4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazines-2; 4-bis-base) two (urea two base)) two (caprylyl)) two (urea two base)) two (1-carboxyl pentane-5,1-bis-base)) two (urea two base)) two (carbonyl)) two (urea two base)) diglutaric acid lutetium complex.
To solid (((2S, 2'S)-2, 2'-(((((1S, 1'S)-((8, 8'-((6-((4-((1, 4, 7, 10-tetra-(carboxymethyl group)-1, 4, 7, 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1, 3, 5-triazine-2, 4-bis-base) two (urea two base)) two (caprylyl)) two (urea two base)) two (1-carboxyl pentane-5, 1-bis-base)) two (urea two base)) two (carbonyl)) two (urea two base)) diglutaric acid (8.5mg, LuCl is added 0.005646mmol)
3(1.47mL, 0.00385mmol/mL, 0.005646mmol).At 70 DEG C, reacting by heating mixture continues 1 hour, lyophilizing subsequently, obtain white solid (2S, 2'S)-2, 2'-(((((1S, 1'S)-((8, 8'-((6-((4-((1, 4, 7, 10-tetra-(carboxymethyl group)-1, 4, 7, 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1, 3, 5-triazine-2, 4-bis-base) two (urea two base)) two (caprylyl)) two (urea two base)) two (1-carboxyl pentane-5, 1-bis-base)) two (urea two base)) two (carbonyl)) two (urea two base)) diglutaric acid lutetium complex (8.6mg).MS(ESI),1678.0(M+H)
+。
Embodiment 7. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (S)-di-t-butyl 2-(3-((S)-6-(11-(4-((benzyloxy) carbonyl) piperazine-1-base) undecanoyl amido)-1-(tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate.
At room temperature stir (S)-di-t-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate (1.023g, 2.097mmol), 11-(4-((benzyloxy) carbonyl) piperazine-1-base) hendecanoic acid (0.77g, 1.9059mmol), EDCI (0.40g, 2.097mmol), dichloromethane (the DCE of HOBt (0.27g, 2.097mmol) and DIPEA (1.0mL); 25mL) solutions overnight.Next day, solvent is evaporated, obtain residue, described residue uses the mixture of Biotage column chromatography and DCM/MeOH to carry out purification as eluant, obtain light yellow solid (S)-di-t-butyl 2-(3-((S)-6-(11-(4-((benzyloxy) carbonyl) piperazine-1-base) undecanoyl amido)-1-(tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate (1.52g, 91%).MS(ESI),874.3(M+H)
+。
Step 2. (S)-di-t-butyl 2-(3-(own-2-base of (S)-1-(tert-butoxy)-1-oxygen-6-(11-(piperazine-1-base) undecanoyl amido)) urea groups) glutarate.
Palladium carbon (300mg) is added in ethanol (60mL) solution of (S)-di-t-butyl 2-(3-((S)-6-(11-(4-((benzyloxy) carbonyl) piperazine-1-base) undecanoyl amido)-1-(tert-butoxy)-1-oxygen hexane-2-base) urea groups) glutarate (1.50g, 1.72mmol) and ammonium formate (1.0g).At room temperature stirred reaction mixture spends the night, and is filtered by Celite pad, uses ethyl acetate (EtOAc) to wash Celite pad subsequently.At reduced pressure conditions except desolventizing, and residue is dissolved in dichloromethane (DCM).Use saturated sodium bicarbonate washing DCM solution, DCM solution is assigned to organic layer separately and water layer subsequently.Concentration of organic layers at reduced pressure conditions, obtains light yellow solid title product (1.2345g, 97% productive rate).MS(ESI),740.4(M+H)
+。
Step 3. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) with cyanuric chloride (9.2mg, add DIPEA (0.10mL) in DCM (2.0mL) solution 0.050mmol), and at room temperature stir the mixture that obtains and continue 2 hours.After stirring, under nitrogen flowing except desolventizing, obtain residue, this residue is dissolved in DMSO (1.0mL), add (S)-di-t-butyl 2-(3-(own-2-base of (S)-1-(tert-butoxy)-1-oxygen-6-(11-(piperazine-1-base) undecanoyl amido)) urea groups) glutarate (34mg, 0.05mmol) and K subsequently
2cO
3(50mg).At room temperature stir the suspension lasts that obtains 2 hours, add the tetrahydrofuran solution of dimethylamine subsequently.At room temperature stirred reaction mixture 16 hours again, lyophilizing is reacted, and obtains thick triazine intermediate.Deprotection use TFA (2.0mL) of crude product and DCM (1.0mL) at room temperature spend the night and carry out.Next day, under nitrogen flowing except desolventizing, obtain residue, this residue is by Biotage SP4, C18 cylinder is used to carry out purification, obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazines-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid (24mg).MS(ESI),601.2(M/2+H)
+。
Step 4. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) add LuCl in 1,3-propanedicarboxylic acid (9.4mg, 0.00783mmol)
3(1.02mL, 0.00770mmol/mL, 0.00783mmol).At 90 DEG C, reacting by heating mixture continues 1 hour, lyophilizing subsequently, obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex (11.1mg).MS(ESI),1373.7(M+H)
+。
Embodiment 8. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. ((2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) and add DIPEA (0.10mL) in DCM (2.0mL) solution of cyanuric chloride (9.2mg, 0.050mmol) and at room temperature agitating solution 2 hours.Use nitrogen current except desolventizing subsequently, obtain residue, this residue is dissolved in DMSO (1.0mL), adds piperidines (4.25mg, 0.05mmol) subsequently.At room temperature stir the suspension lasts that obtains 2 hours, subsequently by (S)-di-t-butyl 2-(3-(own-2-base of (S)-1-(tert-butoxy)-1-oxygen-6-(11-(piperazine-1-base) undecanoyl amido)) urea groups) glutarate (37mg, 0.05mmol) and K
2cO
3(50mg) add in DMSO solution.After at room temperature stirring 16 hours, lyophilizing mixture, obtains thick triazine intermediate again, and this triazine intermediate uses TFA (2.0mL) and DCM (1.0mL) to carry out deprotection.Spend the night carry out deprotection by room temperature stirring crude product, and use next day nitrogen current to remove desolventizing, obtain residue, this residue is by Biotage SP4, C18 cylinder is used to carry out purification, obtain white solid ((2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1, 4, 7, 10-tetra-(carboxymethyl group)-1, 4, 7, 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1, 3, 5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid (22mg).MS(ESI),621.2(M/2+H)
+。
Step 2. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) add LuCl in 1,3-propanedicarboxylic acid (12.4mg, 0.01mmol)
3(1.30mL, 0.00770mmol/mL, 0.01mmol).At 90 DEG C, reacting by heating mixture continues 1 hour, lyophilizing subsequently, obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex (14.0mg).MS(ESI),1413.7(M+H)
+。
Embodiment 9. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-((2-(2-(2-Carboxyethoxy) ethyoxyl) ethyl) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-((2-(2-(2-Carboxyethoxy) ethyoxyl) ethyl) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) and in the DCM solution (2.0mL) of cyanuric chloride (9.2mg, 0.050mmol) add DIPEA (0.10mL).After at room temperature stirring 2 hours, under nitrogen flowing except desolventizing, obtain residue, this residue is dissolved in DMSO (1.0mL).Subsequently by tert-butyl group 3-(2-(2-amino ethoxy) ethyoxyl) propionic ester (11.67mg, 0.05mmol) and K
2cO
3(50mg) add in DMSO solution, at room temperature stir the suspension that obtains 2 hours.Add (S)-di-t-butyl 2-(3-(own-2-base of (S)-1-(tert-butoxy)-1-oxygen-6-(11-(piperazine-1-base) undecanoyl amido)) urea groups) glutarate (37mg, 0.05mmol) subsequently.After stirring 16 hours, lyophilizing reactant mixture, obtains thick triazine intermediate, uses TFA (2.0mL) and DCM (1.0mL) to carry out deprotection to this thick triazine intermediate.Spend the night carry out deprotection by room temperature stirring crude product, nitrogen current is used next day to remove desolventizing, obtain residue, this residue is by Biotage SP4, C18 cylinder is used to carry out purification, obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-((2-(2-(2-Carboxyethoxy) ethyoxyl) ethyl) is amino)-6-((4-((1, 4, 7, 10-tetra-(carboxymethyl group)-1, 4, 7, 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1, 3, 5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid (29.4mg).MS(ESI),667.2(M/2+H)
+。
Step 2. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-((2-(2-(2-Carboxyethoxy) ethyoxyl) ethyl) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-((2-(2-(2-Carboxyethoxy) ethyoxyl) ethyl) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) add LuCl in 1,3-propanedicarboxylic acid (13.1mg, 0.01mmol)
3(1.30mL, 0.00770mmol/mL, 0.01mmol).Reacting by heating mixture 1 hour at 90 DEG C, and lyophilizing obtains white solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-((2-(2-(2-Carboxyethoxy) ethyoxyl) ethyl) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex (14.5mg).MS(ESI),1505.7(M+H)
+。
Embodiment 10. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-((26-carboxyl-3,6,9,12,15, the pungent cerul of 18,21,24-) amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazines-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-((26-carboxyl-3,6,9,12,15, the pungent cerul of 18,21,24-) amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazines-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) and in DCM (2.0mL) solution of cyanuric chloride (9.2mg, 0.050mmol) add DIPEA (0.10mL).At room temperature stirring reaction continues 2 hours, uses nitrogen current except desolventizing subsequently.The residue obtained thus to be dissolved in DMSO (1.0mL) and by amino for 1--3,6,9,12,15,18,21,24-pungent 26 carbon-27-alkanoic acid (22.1mg, 0.05mmol) and K
2cO
3(50mg) add in DMSO solution.At room temperature stir the suspension that obtains 2 hours, add (S)-di-t-butyl 2-(3-(own-2-base of (S)-1-(tert-butoxy)-1-oxygen-6-(11-(piperazine-1-base) undecanoyl amido)) urea groups) glutarate (37mg, 0.05mmol) subsequently.After at room temperature stirring 16 hours, lyophilizing crude reaction, obtains triazine intermediate again, at room temperature, uses TFA (2.0mL) and DCM (1.0mL) to carry out deprotection to described triazine intermediate.By Biotage SP4, C18 cylinder is used to carry out purification to crude product, obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-((26-carboxyl-3,6,9,12,15, the pungent cerul of 18,21,24-) amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazines-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid (31.4mg).MS(ESI),799.3(M/2+H)
+。
Step 2. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-((26-carboxyl-3,6,9,12,15, the pungent cerul of 18,21,24-) amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazines-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
By LuCl
3(0.69mL of a 0.00770mmol/mL, 0.00532mmol) add to solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-((26-carboxyl-3,6,9,12,15,18, the pungent cerul of 21,24-) amino)-6-((4-((Isosorbide-5-Nitrae, 7,10-tetra-(carboxymethyl group)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) in 1,3-propanedicarboxylic acid (8.5mg, 0.00532mmol).Reacting by heating mixture 1 hour at 90 DEG C, lyophilizing subsequently, obtain white solid 2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-((26-carboxyl-3,6,9,12,15, the pungent cerul of 18,21,24-) amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazines-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex (8.2mg).MS(ESI),885.2(M/2+H)
+。
Embodiment 11. (2S)-2-(3-((1S)-5-(11-(4-(4-(((S)-5-(two ((1-(carboxymethyl group)-1H-imidazoles-2-base) methyl) is amino)-1-carboxy pentyl) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (2S)-2-(3-((1S)-5-(11-(4-(4-(((S)-5-(two ((1-(carboxymethyl group)-1H-imidazoles-2-base) methyl) is amino)-1-carboxy pentyl) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) and in DCM (2.0mL) solution of cyanuric chloride (9.2mg, 0.050mmol) add DIPEA (0.10mL).After at room temperature stirring 2 hours, use nitrogen current except desolventizing, obtain residue.This residue is dissolved in DMSO (1.0mL) and also adds (S)-2-amino-6-(two ((1-(2-(tert-butoxy)-2-oxo ethyl)-1H-imidazoles-2-base) methyl) is amino) caproic acid (26.7mg, 0.05mmol) and K subsequently
2cO
3(50mg).At room temperature stir the suspension obtained to spend the night.Next day, add (S)-di-t-butyl 2-(3-((S)-1-(tert-butoxy)-1-oxygen-6-(11-(piperazine-1-base) undecanoyl amido) oneself-2-base) urea groups) glutarate (37mg, 0.05mmol) and at room temperature stirred reaction mixture 24 hours again.Lyophilizing obtains thick triazine intermediate, uses TFA (3.0mL) and DCM (1.0mL) at room temperature to spend the night and carries out deprotection.The thick end product of deprotection is by Biotage SP4, C18 cylinder is used to carry out purification, obtain white solid (2S)-2-(3-((1S)-5-(11-(4-(4-(((S)-5-(two ((1-(carboxymethyl group)-1H-imidazoles-2-base) methyl) is amino)-1-carboxy pentyl) is amino)-6-((4-((1, 4, 7, 10-tetra-(carboxymethyl group)-1, 4, 7, 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1, 3, 5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid (41.5mg).MS(ESI),789.6(M/2+H)
+。
Step 2. (2S)-2-(3-((1S)-5-(11-(4-(4-(((S)-5-(two ((1-(carboxymethyl group)-1H-imidazoles-2-base) methyl) is amino)-1-carboxy pentyl) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((1S)-5-(11-(4-(4-(((S)-5-(two ((1-(carboxymethyl group)-1H-imidazoles-2-base) methyl) is amino)-1-carboxy pentyl) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) add LuCl in 1,3-propanedicarboxylic acid (16.3mg, 0.0103mmol)
3(1.0mL, 0.0103mmol/mL, 0.0103mmol).At 90 DEG C, reacting by heating mixture continues 1 hour, lyophilizing subsequently, obtain white solid (2S)-2-(3-((1S)-5-(11-(4-(4-(((S)-5-(two ((1-(carboxymethyl group)-1H-imidazoles-2-base) methyl) is amino)-1-carboxy pentyl) is amino)-6-((4-((1, 4, 7, 10-tetra-(carboxymethyl group)-1, 4, 7, 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1, 3, 5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid lutetium complex (15.7mg).MS(ESI),875.6(M/2+H)
+。
Embodiment 12. (2S)-2-(3-((1S)-5-(11-(4-(4-(two (carboxymethyl group) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (2S)-2-(3-((1S)-5-(11-(4-(4-(two (carboxymethyl group) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) with cyanuric chloride (9.2mg, add DIPEA (0.10mL) in DCM (2.0mL) solution 0.050mmol), and at room temperature stir the mixture that obtains and continue 2 hours.Use nitrogen current to obtain residue except desolventizing, this residue is dissolved in DMSO (1.0mL), adds di-t-butyl 2,2'-urea two base diacetate esters (24.5mg, 0.10mmol) and K subsequently
2cO
3(50mg).At room temperature stir the suspension obtained to spend the night, and next day adds (S)-di-t-butyl 2-(3-((S)-1-(tert-butoxy)-1-oxygen-6-(11-(piperazine-1-base) undecanoyl amido) oneself-2-base) urea groups) glutarate (37mg, 0.05mmol) at room temperature continuous stirring 24 hours.This suspension of lyophilizing, obtains triazine intermediate, at room temperature uses TFA (3.0mL) and DCM (1.0mL) to spend the night and carries out deprotection.The crude product of deprotection is by Biotage SP4; C18 cylinder is used to carry out purification; obtain white solid (2S)-2-(3-((1S)-5-(11-(4-(4-(two (carboxymethyl group) is amino)-6-((4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1; 3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid (27.0mg).MS(ESI),645.2(M/2+H)
+。
Step 2. (2S)-2-(3-((1S)-5-(11-(4-(4-(two (carboxymethyl group) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
By LuCl
3(0.89mL, 0.0103mmol/mL, 0.00915mmol) add to solid reactant (2S)-2-(3-((1S)-5-(11-(4-(4-(two (carboxymethyl group) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) in 1,3-propanedicarboxylic acid (11.8mg, 0.00915mmol).At 90 DEG C, reacting by heating mixture continues 1 hour, lyophilizing subsequently obtains white solid (2S)-2-(3-((1S)-5-(11-(4-(4-(two (carboxymethyl group) is amino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid lutetium complex (12.0mg).MS(ESI),731.2(M/2+H)
+。
Embodiment 13. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(methylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(methylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) and add DIPEA (0.10mL) in DCM (2.0mL) solution of cyanuric chloride (9.2mg, 0.050mmol) and at room temperature agitating solution 2 hours.After stirring, use nitrogen current except desolventizing, obtain residue.This residue is dissolved in DMSO (1.0mL), and makes solution contact methylamine (in 0.10mL, THF 2.0M) and K
2cO
3(50mg).At room temperature stir the suspension that obtains 4 hours.Subsequently by (S)-di-t-butyl 2-(3-(own-2-base of (S)-1-(tert-butoxy)-1-oxygen-6-(11-(piperazine-1-base) undecanoyl amido)) urea groups) glutarate (37mg, 0.05mmol) add in DMSO solution, and at room temperature stirred reaction mixture 24 hours again, lyophilizing subsequently obtains thick triazine intermediate.Use TFA (3.0mL) and DCM (1.0mL) at room temperature to spend the night and carry out deprotection, subsequently, use nitrogen current except desolventizing, obtain crude product, this crude product is by Biotage SP4, C18 cylinder is used to carry out purification, obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(methylamino)-6-((4-((1, 4, 7, 10-tetra-(carboxymethyl group)-1, 4, 7, 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1, 3, 5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid (10.8mg).MS(ESI),594.2(M/2+H)
+。
Step 2. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(methylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(methylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid, LuCl is added in (7.7mg, 0.00649mmol)
3(0.63mL, 0.0103mmol/mL, 0.00649mmol).At 90 DEG C, reacting by heating mixture continues 1 hour, lyophilizing subsequently, obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(methylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex (7.9mg).MS(ESI),680.2(M/2+H)
+。
Embodiment 14. (2S)-2-(3-((1S)-5-(11-(4-(4-(4-(3-aminopropyl) piperazine-1-base)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (2S)-2-(3-((1S)-5-(11-(4-(4-(4-(3-aminopropyl) piperazine-1-base)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050mmol) and add DIPEA (0.10mL) in DCM (2.0mL) solution of cyanuric chloride (9.2mg, 0.050mmol) and at room temperature agitating solution 2 hours.After stirring, under nitrogen flowing except desolventizing, obtain residue, this residue is dissolved in DMSO (1.0mL), add (S)-di-t-butyl 2-(3-(own-2-base of (S)-1-(tert-butoxy)-1-oxygen-6-(11-(piperazine-1-base) undecanoyl amido)) urea groups) glutarate (37mg, 0.05mmol) and K subsequently
2cO
3(50mg).At room temperature stir the suspension that obtains 2 hours, and add 3-(piperazine-1-base) third-1-amine (47mg) subsequently, subsequently at room temperature stirred reaction mixture 16 hours again.Lyophilizing after 16 hours, obtains thick triazine intermediate, at room temperature uses TFA (2.0mL) and DCM (1.0mL) to spend the night and carries out deprotection.The product of deprotection is by Biotage SP4; C18 cylinder is used to carry out purification; obtain white solid (2S)-2-(3-((1S)-5-(11-(4-(4-(4-(3-aminopropyl) piperazine-1-base)-6-((4-((1; 4; 7; 10-tetra-(carboxymethyl group)-1; 4; 7; 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1; 3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid (25mg).MS(ESI),650.3(M/2+H)
+。
Step 2. (2S)-2-(3-((1S)-5-(11-(4-(4-(4-(3-aminopropyl) piperazine-1-base)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((1S)-5-(11-(4-(4-(4-(3-aminopropyl) piperazine-1-base)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) add LuCl in 1,3-propanedicarboxylic acid (10.7mg, 0.00824mmol)
3(0.80mL, 0.0103mmol/mL, 0.00824mmol).Reacting by heating mixture 1 hour at 90 DEG C, lyophilizing subsequently, obtain white solid (2S)-2-(3-((1S)-5-(11-(4-(4-(4-(3-aminopropyl) piperazine-1-base)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido)-1-carboxy pentyl) urea groups) 1,3-propanedicarboxylic acid lutetium complex (10.2mg).MS(ESI),736.2(M/2+H)
+。
Embodiment 15. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(4-(carboxymethyl group) piperazine-1-base)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(4-(carboxymethyl group) piperazine-1-base)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics), (42.4mg, 0.050mmol) with cyanuric chloride (9.2mg, add DIPEA (0.10mL) in DCM solution (2.0mL) 0.050mmol), at room temperature stir the solution that obtains 2 hours.After stirring, use nitrogen current except desolventizing, obtain residue, this residue is dissolved in DMSO (1.0mL), add (S)-di-t-butyl 2-(3-(own-2-base of (S)-1-(tert-butoxy)-1-oxygen-6-(11-(piperazine-1-base) undecanoyl amido)) urea groups) glutarate (37mg, 0.05mmol) and K subsequently
2cO
3(50mg).At room temperature stir the suspension that obtains thus 2 hours, and subsequently tert-butyl group 2-(piperazine-1-base) acetas (50mg) to be added in reactant mixture and at room temperature continuous stirring 16 hours again.Lyophilizing reactant mixture at the end of 16 hours, obtains the end product residue protected.This residue is at room temperature contacted with DCM (1.0mL) with TFA (2.0mL) spend the night, thus removing blocking group, subsequently; under nitrogen flowing except desolventizing; obtain thick deprotection product, this product, by Biotage SP4, uses C18 cylinder to carry out purification.Obtain titled compound as white solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(4-(carboxymethyl group) piperazine-1-base)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid (14mg).MS(ESI),650.8(M/2+H)
+。
Step 2. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(4-(carboxymethyl group) piperazine-1-base)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(4-(carboxymethyl group) piperazine-1-base)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) add LuCl in 1,3-propanedicarboxylic acid (6.0mg, 0.00426mmol)
3(0.45mL, 0.0103mmol/mL, 0.00462mmol).Reacting by heating mixture 1 hour at 90 DEG C, and lyophilizing obtains white solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(4-(carboxymethyl group) piperazine-1-base)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex (5.6mg).MS(ESI),736.8(M/2+H)
+。
Embodiment 16. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(4-(3-carboxypropyl) piperidin-1-yl)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
Step 1. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(4-(3-carboxypropyl) piperidin-1-yl)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid.
To p-NH2-Bn-DOTA-tetra-(t-Bu-ester) (Macrocyclics), (42.4mg, 0.050mmol) and in DCM (2.0mL) solution of cyanuric chloride (9.2mg, 0.050mmol) add DIPEA (0.10mL).After at room temperature stirring 2 hours, use nitrogen current except desolventizing, obtain residue, this residue is dissolved in DMSO (1.0mL), add (S)-di-t-butyl 2-(3-(own-2-base of (S)-1-(tert-butoxy)-1-oxygen-6-(11-(piperazine-1-base) undecanoyl amido)) urea groups) glutarate (37mg, 0.05mmol) and K subsequently
2cO
3(50mg).At room temperature stir the suspension 2 hours of formation, and subsequently 4-(piperidin-4-yl) butanoic acid (160mg) is added in suspension.At room temperature after continuous stirring 72 hours, by lyophilizing stopped reaction, obtain the triaizine compounds protected.At room temperature use TFA (4.0mL) and DCM (1.0mL) to spend the night and carry out deprotection, Biotage SP4 and C18 cylinder is used to carry out purification subsequently, obtain white solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(4-(3-carboxypropyl) piperidin-1-yl)-6-((4-((1, 4, 7, 10-tetra-(carboxymethyl group)-1, 4, 7, 10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1, 3, 5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid (15.3mg).MS(ESI),650.8(M/2+H)
+。
Step 2. (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(4-(3-carboxypropyl) piperidin-1-yl)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex.
To solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(4-(3-carboxypropyl) piperidin-1-yl)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) add LuCl in 1,3-propanedicarboxylic acid (6.9mg, 0.00520mmol)
3(0.50mL, 0.0103mmol/mL, 0.00520mmol).Reacting by heating mixture 1 hour at 90 DEG C, and lyophilizing obtains white solid (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(4-(3-carboxypropyl) piperidin-1-yl)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid lutetium complex (7.9mg).MS(ESI),750.2(M/2+H)
+。
Embodiment 17.
68ga labelling (2S)-2-(3-((1S)-1-carboxyl-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetra-(carboxymethyl group)-1,4,7,10-tetraazacyclododecanand-2-base) methyl) phenyl) amino)-1,3,5-triazine-2-base) piperazine-1-base) undecanoyl amido) amyl group) urea groups) 1,3-propanedicarboxylic acid.
Use gallium-68 maker (IDB Holland) synthesis
68ga.1mL is contained the highest
68(using the pure HCl of 0.6M supra to carry out eluting) and the reaction mixture containing 2 μ L target compounds (the DMSO solution of 10mM) and 10 μ l ascorbic acid (in water 20%) of the maker eluent of Ga activity.By adding the aqueous solution (in water 2.5M) of the sodium acetate of about 290 μ L by the pH scope of the pH regulator to 3.6 of reactant mixture to 3.9.
Under 90 DEG C of conditions, heated and stirred mixture 10 minutes.By the test sample of HPLC analyze reaction mixture to determine that complexation is complete.Use 2ml saline (0.9% sodium chloride) diluted reaction mixture subsequently and be loaded on the Plexa cylinder (60mg, Varian, Bond Elut Plexa) regulated in advance.With this cylinder of 2ml saline rinse, use the complex that 0.5ml ethanol elution is expected subsequently.Eluent flows through the sterilizing filter (Millipore, Millex-GV) being assemblied in syringe, makes 5ml saline and 200 μ l phosphate buffers flow through filter with washing filter subsequently.
Radiolabeled compound is by Chromolith Performance RP-18e post (100 × 3mmMerck KGaA, Darmstadt, Germany) HPLC on, uses the acetonitrile solution (all comprising 0.1%TFA) of 0% to 100% linear gradient to carry out analysis and continues 5 minutes.Detect the UV absorbance of 214nm.Under these conditions, at about 2.25min eluting
68ga-MIP-1558.Radio chemistry productive rate is 77% to 97%, average RCP=87% (by cooling correction data).
Equivalents
Although illustrate and described some embodiments herein, but should be understood that, do not deviating from accompanying claims from the condition of broadly limited technical scheme, art technology those of ordinary skill can change embodiment herein and improve.
Content disclosed by the invention is not limited to the particular implementation that the application describes.Can make many improvement and change to these embodiments under the condition not deviating from the spirit and scope of the invention, this is obvious to those skilled in the art.In the scope of content disclosed herein, except method and composition cited herein, by description above, equivalent processes functionally and compositions are obvious to those skilled in the art.These improvement and change are intended to fall in the scope of appended claim.Content disclosed herein limits only by the four corner of the term of appended claim and the equivalent of these terms.Should be understood that, content disclosed herein is not limited to ad hoc approach, reagent, compound composition or biosystem, and these ad hoc approach, reagent, compound composition or biosystem can change certainly.It is to be further understood that term used herein is only used to describe particular implementation, be not intended to limit the present invention.
In addition, describe with Ma Kushi group feature disclosed herein or in condition under, one skilled in the art will recognize that content disclosed herein also describes according to the subset of any separate member in Ma Kushi group or member.
As understood by those skilled in the art, for any and all objects, especially according to provided written description content, all scopes disclosed herein also comprise the combination of any and all possible subrange and subrange.Any scope enumerated can be easy to be understood as that to be enough to describe identical scope and identical scope can be made to resolve at least two equal portions, three equal parts, quarter, five equal portions, ten equal portions, etc.As the embodiment of indefiniteness, each scope discussed in this article can be easy to resolve into down 1/3rd, middle 1/3rd and upper 1/3rd, etc.As understood by those skilled in the art, such as " up to ", " at least ", " higher than ", " lower than " etc. all language comprise described numeral and refer to the scope that can be broken down into above-mentioned subrange subsequently.Finally, as understood by those skilled in the art, scope comprises each independent member, comprises first digit cited in scope and last numeral.
All public publications referenced in this description, patent application, granted patent and alternative document are incorporated to herein by reference, each independently patent of public publication, patent application, mandate or the full content of alternative document are incorporated to by reference herein as special and independent explanation.The definition comprised in the content be incorporated to by reference eliminates the content with content contradiction disclosed by the invention.
Claim enumerating other embodiments accompanying.
Claims (29)
1. the compound according to general formula I:
Wherein:
A is (CHR
1)
mor C (O);
W Shi – C (O) – (CH
2)
p-;-C (O) [-CH
2-CH
2-O]
n-,-[CH
2-CH
2-O]
n-(CH
2)
2-， – C (O)-[CH (R
3)
t]
q-,-(CH
2)
m-O-(CH
2)
n-,-(CH
2)
m-S-(CH
2)
n-,-(CH
2)
m-S (O)-(CH
2)
n-,-(CH
2)
m-S (O)
2-(CH
2)
n-, or-(CH
2)
m-NR
a-(CH
2)
n-,
Y Shi – NH-,-NR
2-, or
X Shi – (C
1-C
10) alkylidene-(C
3-C
10) arlydene ,-(C
3-C
10) arlydene ,-(C
3-C
10) Ya Fangji – (C
1-C
10) alkylidene-, phenylene ， – (C
1-C
10) alkylidene-(C
3-C
10) ring alkylidene ,-(C
3-C
10) ring alkylidene, or-(C
3-C
10) ring Ya Wan Ji – (C
1-C
10) alkylidene-;
R
1and R
2separately H ,-(C
1-C
10) alkyl ， – C (O)-(C
1-C
10) alkyl, benzyl ,-(C
3-C
10) cycloalkyl, or-(C
3-C
10) aryl;
R
aand R
bseparately H ,-OH ,-(C
1-C
10) alkyl ,-[CH
2-CH
2-O]
n-(CH
2)
2-T ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-Z, benzyl ,-(C
3-C
10) cycloalkyl ,-(C
3-C
10) aryl-(C
1-C
10) alkylidene ,-(C
3-C
10) aryl, halo-(C
1-C
10) alkyl, hydroxyl-(C
1-C
10) alkyl ,-NH--(C
1-C
10) alkyl, or-(C
1-C
10) alkylidene-NR
dr
e-, or R
aand R
band nitrogen bonded thereto together forms (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl, (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl can comprise further and is selected from N, one or more than one hetero atom of S or O;
Z Shi – OH ,-O (C
1-C
10) alkyl,
R
c-OH ,-O (C
1-C
10) alkyl ,-O benzyl ,-O (C
3-C
10) cycloalkyl ,-O (C
3-C
10) aryl ,-O-(C
1-C
10) alkylidene-(C
3-C
10) aryl, or-O-(C
1-C
10) alkylidene--(C
3-C
10) cycloalkyl,
R
3h, halogen ,-OH ,-NH
2， – (CH
2)
p-COOH ， Huo – (CH
2)
p-NH
2;
T Shi – H ， – OH ,-COOH ， Huo – NR
dr
e;
R
dand R
eseparately H, chemical bond ,-OH ,-(C
1-C
10) alkyl, or-(C
3-C
10) heteroaryl-(C
1-C
10) alkylidene;
M, n, p, q, t and r are separately 0,1,2,3,4,5,6,7,8,9 or 10; And
D is
Wherein, any alkyl, alkylidene, aryl, arlydene, heteroaryl, heteroarylidene, cycloalkyl, ring alkylidene, Heterocyclylalkyl, or heterocycloalkylene group is optionally by 1, and 2, or 3 substituent groups being selected from following groups replace :-(C
1-C
10) alkyl ,-(C
1-C
10) haloalkyl ,-(C
1-C
10) aminoalkyl ,-(C
1-C
10) alkylidene-COOH ,-(C
1-C
10) hydroxy alkyl ,-OH, halogen ,-NH
2,-COOH ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-X ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-， is with – NR
dr
e.
2. compound as claimed in claim 1, wherein, X is phenylene, and r is 1,
And D is
3. compound as claimed in claim 2, wherein, described compound is the compound according to general formula I I:
Wherein:
A is (CHR
1)
mor C (O);
W is selected from: – C (O) – (CH
2)
p-;-C (O) [-CH
2-CH
2-O]
n-,-[CH
2-CH
2-O]
n-(CH
2)
2-， – C (O)-[CH (R
3)
t]
q-,-(CH
2)
m-O-(CH
2)
n-,-(CH
2)
m-S-(CH
2)
n-,-(CH
2)
m-S (O)-(CH
2)
n-,-(CH
2)
m-S (O)
2-(CH
2)
n-, and-(CH
2)
m-NR
a-(CH
2)
n-,
Y is selected from: – NH-,-NR
2-,
R
1and R
2separately be selected from: H ,-(C
1-C
10) alkyl ， – C (O)-(C
1-C
10) alkyl, benzyl ,-(C
3-C
10) cycloalkyl, or-(C
3-C
10) aryl;
R
aand R
bseparately be selected from: H ,-OH ,-(C
1-C
10) alkyl ,-[CH
2-CH
2-O]
n-(CH
2)
2-T ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-Z, benzyl ,-(C
3-C
10) cycloalkyl ,-(C
3-C
10) aryl-(C
1-C
10) alkylidene ,-(C
3-C
10) aryl, halo-(C
1-C
10) alkyl, hydroxyl-(C
1-C
10) alkyl ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-, or R
aand R
band nitrogen bonded thereto together forms (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl, (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl can comprise further and is selected from N, one or more than one hetero atom of S or O;
Z is selected from: – OH ,-O (C
1-C
10) alkyl,
R
cbe selected from :-OH ,-O (C
1-C
10) alkyl ,-O benzyl ,-O (C
3-C
10) cycloalkyl ,-O (C
3-C
10) aryl ,-O-(C
1-C
10) alkylidene--(C
3-C
10) aryl, or-O-(C
1-C
10) alkylidene--(C
3-C
10) cycloalkyl,
R
3be selected from: H, halogen ,-OH ,-NH
2， – (CH
2)
p-COOH ， Huo – (CH
2)
p-NH
2;
T is selected from: – H ， – OH ,-COOH ， Huo – NR
dr
e;
R
dand R
eseparately be selected from: H, chemical bond ,-OH ,-(C
1-C
10) alkyl, or-(C
3-C
10) heteroaryl-(C
1-C
10) alkylidene;
M, n, p, q, t and x are separately 0,1,2,3,4,5,6,7,8,9 or 10;
Wherein any alkyl, alkylidene, aryl, arlydene, heteroaryl, heteroarylidene, cycloalkyl, ring alkylidene, Heterocyclylalkyl, or heterocycloalkylene group is by 1, and 2, or 3 substituent groups being selected from following groups optionally replace :-(C
1-C
10) alkyl ,-(C
1-C
10) haloalkyl ,-(C
1-C
10) aminoalkyl ,-(C
1-C
10) alkylidene-COOH ,-(C
1-C
10) hydroxy alkyl ,-NH
2,-COOH ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-X ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-， is with – NR
dr
e.
4. compound as claimed in claim 3, wherein, A is (CHR
1)
mand W Shi – C (O) – (CH
2)
p-.
5. compound as claimed in claim 4, wherein, W is-C (O)-(CH
2)
7-or-C (O)-(CH
2)
10-.
6. compound as claimed in claim 4, wherein, R
1be hydrogen and m is 2.
7. compound as claimed in claim 3, wherein, Y Shi – NH-or
8. compound as claimed in claim 7, wherein, Y is
9. compound as claimed in claim 3, wherein, R
aand R
bbe separately hydrogen or methyl and R
cshi – OH.
10. compound as claimed in claim 3, wherein, R
aand R
band nitrogen bonded thereto together forms (C
3-C
6)-Heterocyclylalkyl.
11. compounds as claimed in claim 10, wherein, (C
3-C
6)-Heterocyclylalkyl is selected from: piperidines, piperazine, morpholine, thiomorpholine, isothiazolidine, isoxazole alkane, pyrrolidine, imidazolidine, Thiazolidine or oxazolidine.
12. compounds as claimed in claim 11, wherein, (C
3-C
6)-Heterocyclylalkyl is piperidines or 4-(piperidin-4-yl) butanoic acid.
13. compounds as claimed in claim 10, wherein, R
ashi – H, and
R
bbe
14. compounds as claimed in claim 10, wherein, R
dand R
eseparately-(C
3-C
10) heteroaryl-(C
1-C
10) alkylidene.
15. compounds as claimed in claim 10, wherein, R
dand R
ebe separately
16. compounds as claimed in claim 3, it is selected from following compounds or its pharmaceutically acceptable salt, solvate or ester.
17. 1 kinds of metal complexs, it comprises radionuclide and compound according to claim 1.
18. metal complexs as claimed in claim 17, wherein, described compound is
Wherein:
A is (CHR
1)
mor C (O);
W is selected from: – C (O) – (CH
2)
p-;-C (O) [-CH
2-CH
2-O]
n-,-[CH
2-CH
2-O]
n-(CH
2)
2-， – C (O)-[CH (R
3)
t]
q-,-(CH
2)
m-O-(CH
2)
n-,-(CH
2)
m-S-(CH
2)
n-,-(CH
2)
m-S (O)-(CH
2)
n-,-(CH
2)
m-S (O)
2-(CH
2)
n-and-(CH
2)
m-NR
a-(CH
2)
n-,
Y is selected from: – NH-,-NR
2-,
R
1and R
2separately be selected from: H ,-(C
1-C
10) alkyl ， – C (O)-(C
1-C
10) alkyl, benzyl ,-(C
3-C
10) cycloalkyl, or-(C
3-C
10) aryl;
R
aand R
bseparately be selected from following groups: H ,-OH ,-(C
1-C
10) alkyl ,-[CH
2-CH
2-O]
n-(CH
2)
2-T ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-Z, benzyl ,-(C
3-C
10) cycloalkyl ,-(C
3-C
10) aryl-(C
1-C
10) alkylidene ,-(C
3-C
10) aryl, halo-(C
1-C
10) alkyl, hydroxyl-(C
1-C
10) alkyl ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-, or R
aand R
band nitrogen bonded thereto together forms (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl, (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl can comprise further and is selected from N, one or more than one hetero atom of S or O;
Z is selected from: – OH ,-O (C
1-C
10) alkyl,
R
cbe selected from :-OH ,-O (C
1-C
10) alkyl ,-O benzyl ,-O (C
3-C
10) cycloalkyl ,-O (C
3-C
10) aryl ,-O-(C
1-C
10) alkylidene--(C
3-C
10) aryl, or-O-(C
1-C
10) alkylidene--(C
3-C
10) cycloalkyl,
R
3be selected from: H, halogen ,-OH ,-NH
2， – (CH
2)
p-COOH ， Huo – (CH
2)
p-NH
2;
T is selected from: – H ， – OH ,-COOH ， Huo – NR
dr
e;
R
dand R
eseparately be selected from: H, chemical bond ,-OH ,-(C
1-C
10) alkyl, or-(C
3-C
10) heteroaryl-(C
1-C
10) alkylidene;
M, n, p, q, t and x are separately 0,1,2,3,4,5,6,7,8,9 or 10;
Wherein any alkyl, alkylidene, aryl, arlydene, heteroaryl, heteroarylidene, cycloalkyl, ring alkylidene, Heterocyclylalkyl, or heterocycloalkylene group is by 1,2 or 3 substituent groups being selected from following groups optionally replace :-(C
1-C
10) alkyl ,-(C
1-C
10) haloalkyl ,-(C
1-C
10) aminoalkyl ,-(C
1-C
10) alkylidene-COOH ,-(C
1-C
10) hydroxy alkyl ,-NH
2,-COOH ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-X ,-NH--(C
1-C
10) alkyl, and-(C
1-C
10) alkylidene-NR
dr
e-， is with – NR
dr
e; And
Radionuclide is selected from:
111in,
90y,
68ga,
64cu
153gd,
155gd,
157gd,
59fe,
225ac,
212bi,
213bi,
55co,
67cu,
165dy,
166ho,
192ir,
223ra,
186re,
188re,
105rh,
212pb,
213pb,
149tb,
227th,
153sm,
89sr,
117msn,
169yb,
90y,
86y,
89zr and
177lu.
19. metal complexs as claimed in claim 18, it is following metal complex or its pharmaceutically acceptable salt or solvate.
20. 1 kinds of pharmaceutical compositions, it comprises compound according to claim 3 or its pharmaceutically acceptable salt, solvate or ester, and pharmaceutically acceptable carrier.
21. 1 kinds of pharmaceutical compositions, it comprises metal complex according to claim 18 or its pharmaceutically acceptable salt, solvate or ester, and pharmaceutically acceptable carrier.
The method of the Radionuclide imaging image of one or more than one tissue of prostate specific membrane antigen (PSMA) is expressed in 22. 1 kinds of acquisitions, and described method comprises:
Make one or more than one tissue of expression PSMA and comprise radionuclide and contact with according to the compound of general formula III or the metal complex of its pharmaceutically acceptable salt or solvate; And
Record the Radionuclide imaging image of one or more than one tissue;
Wherein G is
L Shi – NH-(C
1-C
10) alkylidene-， – NH-(C
1-C
10) alkylidene-C (O)-， – C (O)-(C
1-C
10) alkylidene-， – C (O)-(C
1-C
10) alkylidene-C (O)-or
R
aand R
bseparately H ,-OH ,-(C
1-C
10) alkyl ,-[CH
2-CH
2-O]
n-(CH
2)
2-T ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-Z, benzyl ,-(C
3-C
10) cycloalkyl ,-(C
3-C
10) aryl-(C
1-C
10) alkylidene ,-(C
3-C
10) aryl, halo-(C
1-C
10) alkyl, hydroxyl-(C
1-C
10) alkyl ,-NH--(C
1-C
10) alkyl, or-(C
1-C
10) alkylidene-NR
dr
e-, or R
aand R
band nitrogen bonded thereto together forms (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl, (C
3-C
6)-heteroaryl or (C
3-C
6)-Heterocyclylalkyl can comprise further and is selected from N, one or more than one hetero atom of S or O;
Z Shi – OH ,-O (C
1-C
10) alkyl,
R
dand R
eseparately H, chemical bond ,-OH ,-(C
1-C
10) alkyl, or-(C
3-C
10) heteroaryl-(C
1-C
10) alkylidene;
N is 0,1,2,3,4,5,6,7,8,9 or 10; And
Wherein any alkyl, alkylidene, aryl, arlydene, heteroaryl, heteroarylidene, cycloalkyl, ring alkylidene, Heterocyclylalkyl, or heterocycloalkylene group is by 1,2 or 3 substituent groups being selected from following groups optionally replace :-(C
1-C
10) alkyl ,-(C
1-C
10) haloalkyl ,-(C
1-C
10) aminoalkyl ,-(C
1-C
10) alkylidene-COOH ,-(C
1-C
10) hydroxy alkyl ,-NH
2,-COOH ， – C (O)-(C
1-C
10) alkyl ， – (C
1-C
10) alkylidene-C (O)-， – (C
1-C
10) alkylidene-C (O)-X ,-NH--(C
1-C
10) alkyl, or-(C
1-C
10) alkylidene-NR
dr
e-， is with – NR
dr
e.
23. methods as claimed in claim 22, wherein, one or more than one tissue described is selected from prostata tissue or prostate cancer tissue.
24. methods as claimed in claim 22, wherein, described radionuclide is selected from:
111in,
90y,
68ga,
64cu
153gd,
155gd,
157gd,
59fe,
225ac,
212bi,
213bi,
55co,
67cu,
165dy,
166ho,
192ir,
223ra,
186re,
188re,
105rh,
212pb,
213pb,
149tb,
227th,
153sm,
89sr,
117msn,
169yb,
90y,
86y,
89zr and
177lu.
Treat the method that diagnosis suffers from the patient of cancer for 25. 1 kinds, described method comprise by treatment effective dose prostate specific membrane antigen (PSMA) deliver medicine to patient in conjunction with complex, described complex comprises triazine connector, wherein, relative to the tissue of not expressing PSMA, described complex is detained longer interval in the tumor tissues of expressing PSMA.
26. methods as claimed in claim 25, wherein, relative to the tissue of not expressing PSMA, described complex is detained longer interval in the tumor tissues of expressing PSMA, and described tissue of not expressing PSMA is selected from: kidney, liver, spleen, heart, blood, lung, muscle, skeleton, large intestine, small intestinal, brain or fat.
27. methods as claimed in claim 25, wherein, relative to kidney, described complex is detained longer interval in the tumor tissues of expressing PSMA.
28. methods as claimed in claim 25, wherein, described cancer is selected from: carcinoma of prostate, breast carcinoma, colon cancer, the brain cancer, pulmonary carcinoma, hepatocarcinoma, carcinoma of endometrium, osteocarcinoma, ovarian cancer, carcinoma of testis, skin carcinoma, cancer of pancreas, uterus carcinoma, cervical cancer, bladder cancer, esophageal carcinoma, gastric cancer, head and neck cancer or renal carcinoma.
29. methods as claimed in claim 28, wherein, described cancer is carcinoma of prostate.
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| US201361752350P | 2013-01-14 | 2013-01-14 | |
| US61/752,350 | 2013-01-14 | ||
| US201361785788P | 2013-03-14 | 2013-03-14 | |
| US61/785,788 | 2013-03-14 | ||
| PCT/US2014/011047 WO2014110372A1 (en) | 2013-01-14 | 2014-01-10 | Triazine based radiopharmaceuticals and radioimaging agents |
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| EP (4) | EP3300746B1 (en) |
| JP (2) | JP6468602B2 (en) |
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| CN (1) | CN105025933B (en) |
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| CA (1) | CA2897437C (en) |
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| CN109311827A (en) * | 2016-03-22 | 2019-02-05 | 约翰霍普金斯大学 | The high-affinity agent of the prostate-specific membrane antigen targeting of endoradiotherapy for prostate cancer |
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